Anti-cancer phosphonate analogs

ABSTRACT

The invention is related to phosphorus substituted anti-cancer compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

This non-provisional application claims the benefit of priority under 35U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. Nos.60/465,588; 60/465,594; 60/465,465; 60/465,569; 60/465,467; 60/465,631;60/465,714; 60/465,589; 60/465,586; 60/465,607; 60/465,668; 60/465,287;60/465,343; 60/465,471; 60/465,567; 60/465,545; 60/465,394; 60/465,603;60/465,614; 60/465,339; 60/465,325; 60/465,377; 60/465,415; 60/465,575;60/465,844; 60/465,559; 60/495,387; and 60/465,531; all filed Apr. 25,2003; and to U.S. Provisional Patent Application Ser. Nos. 60/493,303and 60/493,310; both filed Aug. 7, 2003; and to U.S. Provisional PatentApplication Ser. Nos. 60/495,382; 60/495,685; 60/495,527; 60/495,686;60/495,525; 60/495,629; 60/495,484; 60/495,644; 60/495,297; 60/495,682;60/495,784; 60/495,751; 60/495,565; 60/495,789; 60/495,736; 60/495,769;60/495,647; 60/495,645; 60/495,362; 60/495,339; 60/495,534; 60/495,669;60/495,425; 60/495,524; 60/495,426; 60/495,393; 60/495,387; and60/495,416; all filed Aug. 15, 2003; and to U.S. Provisional PatentApplication Ser. Nos. 60/514,462; 60/513,971; 60/513,969; 60/514,394;60/514,393; 60/513,944; 60/513,956; 60/513,923; 60/514,202; 60/514,247;60/514,461; 60/514,369; 60/514,452; 60/514,439; 60/513,948; 60/514,424;60/513,972; 60/513,925; 60/513,926; 60/513,927; 60/514,368; 60/514,207;60/514,115; 60/513,980; 60/514,131; 60/514,105; 60/514,280; 60/513,963;60/514,145; 60/514,159; 60/514,083; 60/513,949; 60/514,144; 60/51,4481;60/513,974; 60/514,108; 60/513,979; 60/514,084; 60/514,161; 60/514,304;60/514,235; 60/514,325; 60/514,359; 60/514,113; 60/514,114; 60/514,112;60/513,968; 60/514,345; 60/514,346; 60/513,564; 60/513,588; 60/514,298;60/514,330; 60/513,932; 60/513,976; 60/513,562; 60/514,258; and60/514,258; all filed Oct. 24, 2003; and to U.S. Provisional PatentApplication Ser. No. 60/519,476 and 60/519,476; filed Nov. 12, 2003; andto U.S. Provisional Patent Application Ser. No. 60/524,340; filed Nov.20, 2003; and to U.S. Provisional Patent Application Ser. Nos.60/532,230; 60/531,960; 60/532,160; and 60/531,940; all filed Dec. 22,2003; and to U.S. Provisional Patent Application Ser. No. 60/532,591;filed Dec. 23, 2003; and to U.S. Provisional Patent Application Ser.Nos. 60/536,007; 60/536,006; 60/536,005; 60/536,054 and 60/536,054; allfiled Jan. 12, 2004. The entirety of all Provisional Applications listedabove are incorporated herein by reference; which is incorporated hereinby reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with anti-cancer activity.

BACKGROUND OF THE INVENTION

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the drug with its intracellular target, while minimizingintercellular redistribution of the drug, e.g., to neighboring cells, isoften difficult or inefficient.

Most agents currently administered to a patient parenterally are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., glucocorticoids and other anti-inflammatory drugs) that canbe administered. By comparison, although oral administration of drugs isgenerally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g., blood/brain,epithelial, cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells.

Intracellular targeting may be achieved by methods and compositionswhich allow accumulation or retention of biologically active agentsinside cells.

Many of the current treatment regimes for cell proliferation diseasessuch as psoriasis and cancer utilize compounds which inhibit DNAsynthesis. Such compounds are toxic to cells generally but their toxiceffect on rapidly dividing cells such as tumor cells can be beneficial.Alternative approaches to anti-proliferative agents which act bymechanisms other than the inhibition of DNA synthesis have the potentialto display enhanced selectivity of action.

In recent years it has been discovered that a cell may become cancerousby virtue of the transformation of a portion of its DNA into an oncogenei.e. a gene which, on activation, leads to the formation of malignanttumor cells (Bradshaw, Mutagenesis 1986, 1, 91). Several such oncogenesgive rise to the production of peptides which are receptors for growthfactors. The growth factor receptor complex subsequently leads to anincrease in cell proliferation. It is known, for example, that severaloncogenes encode tyrosine kinase enzymes and that certain growth factorreceptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev.Biochem., 1988, 57, 443; Larsen et al. Ann. Reports in Med. Chem. 1989,Chpt. 13).

Receptor tyrosine kinases are important in the transmission ofbiochemical signals which initiate cell replication. They are largeenzymes which span the cell membrane and possess an extracellularbinding domain for growth factors such as epidermal growth factor (EGF)and an intracellular portion which functions as a kinase tophosphorylate tyrosine amino acids in proteins and hence to influencecell proliferation. Various classes of receptor tyrosine kinases areknown (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based onfamilies of growth factors which bind to different receptor tyrosinekinases. The classification includes Class I receptor tyrosine kinasescomprising the EGF family of receptor tyrosine kinases such as the EGF,TGF.alpha., NEU, erbB, Xmrk, HER and let23 receptors, Class II receptortyrosine kinases comprising the insulin family of receptor tyrosinekinases such as the insulin, IGFI and insulin-related receptor (IRR)receptors and Class III receptor tyrosine kinases comprising theplatelet-derived growth factor (PDGF) family of receptor tyrosinekinases such as the PDGF.alpha., PDGF.beta. and colony-stimulatingfactor 1 (CSF1) receptors. It is known that Class I kinases such as theEGF family of receptor tyrosine kinases are frequently present in commonhuman cancers such as breast cancer (Sainsbury et. al., Brit. J. Cancer,1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn etal., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lungcancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J.Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; andRusch et al., Cancer Research, 1993, 53, 2379) and squamous cell cancerof the lung (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer(Neal et. al., Lancet, 1985, 366), oesophageal cancer (Mukaida et al.,Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal orstomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149), cancer ofthe prostate (Visakorpi et al., Histochem. J., 1992, 24, 481), leukaemia(Konaka et al., Cell, 1984, 37, 1035) and ovarian, bronchial orpancreatic cancer (European Patent Specification No. 0400586). Asfurther human tumor tissues are tested for the EGF family of receptortyrosine kinases it is expected that their widespread prevalence will beestablished in further cancers such as thyroid and uterine cancer. It isalso known that EGF type tyrosine kinase activity is rarely detected innormal cells whereas it is more frequently detectable in malignant cells(Hunter, Cell, 1987, 50, 823). It has been shown more recently (W. J.Gullick, Brit. Med. Bull., 1991, 47, 87) that EGF receptors whichpossess tyrosine kinase activity are overexpressed in many human cancerssuch as brain, lung squamous cell, bladder, gastric, breast, head andneck, oesophageal, gynaecological and thyroid tumors.

Accordingly it has been recognized that an inhibitor of receptortyrosine kinases should be of value as a selective inhibitor of thegrowth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933).Support for this view is provided by the demonstration that erbstatin,an EGF receptor tyrosine kinase inhibitor, specifically attenuates thegrowth in athymic nude mice of a transplanted human mammary carcinomawhich expresses EGF receptor tyrosine kinase but is without effect onthe growth of another carcinoma which does not express EGF receptortyrosine kinase (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26,722.). Various derivatives of styrene are also stated to possesstyrosine kinase inhibitory properties (European Patent Application Nos.0211363, 0304493 and 0322738) and to be of use as anti-tumor agents. Thein vivo inhibitory effect of two such styrene derivatives which are EGFreceptor tyrosine kinase inhibitors has been demonstrated against thegrowth of human squamous cell carcinoma inoculated into nude mice(Yoneda et al., Cancer Research, 1991, 51, 4430). Various known tyrosinekinase inhibitors are disclosed in a more recent review by T. R. BurkeJr. (Drugs of the Future, 1992, 17, 119).

Cancer is a major health problem worldwide. Although drugs targetingtumors and cancerous cells are in wide use and have shown effectiveness,toxicity and side-effects have limited their usefullness.

Assay methods capable of determining the presence, absence or amounts ofcancer are of practical utility in the search for anti-cancer compoundsas well as for diagnosing the presence of cancer.

Inhibitors of tumor growth are useful to limit the establishment andprogression of cancer, as well as in diagnostic assays for cancer.

There is a need for anti-cancer therapeutic agents, i.e. drugs, havingimproved anti-cancer, as well as pharmacokinetic properties, includingenhanced activity against development of cancer, improved oralbioavailability, greater potency and extended effective half-life invivo. Such anti-cancer compounds should be active against variouscancers, have distinct resistance profiles, fewer side effects, lesscomplicated dosing schedules, and orally active. In particular, there isa need for a less onerous dosage regimen, such as one pill, once perday.

SUMMARY OF THE INVENTION

Intracellular targeting may be achieved by methods and compositions thatallow accumulation or retention of biologically active agents insidecells. The present invention provides novel analogs of anti-cancercompounds. Such novel anti-cancer compound analogs possess all theutilities of anti-cancer compounds and optionally provide cellularaccumulation as set forth below. In addition, the present inventionprovides compositions and methods for treating cancer or therapeuticactivity against cancer.

The present invention relates generally to the accumulation or retentionof therapeutic compounds inside cells. The invention is moreparticularly related to attaining high concentrations ofphosphonate-containing molecules in cancer cells. Such effectivetargeting may be applicable to a variety of therapeutic formulations andprocedures.

Accordingly, in one embodiment the invention provides a compound of theinvention which is a conjugate comprising a chemotherapeutic agentlinked to one or more phosphonate groups.

In another embodiment, the invention provides a compound of any one offormulae 500-601:

that is substituted with one or more groups A⁰,wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(b3), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12

In another embodiment, the invention provides a compound of the formula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt or solvate thereof wherein,

DRUG is a compound of any one of formulae 500-601;

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the invention provides a compound of any one offormulae 1-336:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(X)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R², W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M2a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

X⁵⁰ is H F, or Cl; and

X⁵¹ is H or Cl.

The invention provides a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

This invention provides a method of increasing cellular accumulation andretention of drug compounds, thus improving their therapeutic anddiagnostic value, comprising linking the compound to one or more (e.g.,1, 2, 3, or 4) phosphonate groups.

This invention also pertains to a method of increasing cellularaccumulation and retention of a chemotherapeutic agent comprisinglinking the compound to one or more phosphonate groups.

The invention also provides a method of treating cancer in a mammal,comprising administering a compound of the invention to the mammal.

The invention also provides a compound of the invention for use inmedical therapy preferably for use in treating cancer, as well as theuse of a compound of the invention for the manufacture of a medicamentuseful for the treatment of cancer.

In another aspect the invention also provides a method for inhibitingcancer activity comprising contacting a sample in need of such treatmentwith a compound or composition of the invention.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention. The invention also provides novel methods forsyntheses of the compounds of the invention.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Bioavailability” is the degree to which the pharmaceutically activeagent becomes available to the target tissue after the agent'sintroduction into the body. Enhancement of the bioavailability of apharmaceutically active agent can provide a more efficient and effectivetreatment for patients because, for a given dose, more of thepharmaceutically active agent will be available at the targeted tissuesites.

The terms “phosphonate” and “phosphonate group” include functionalgroups or moieties within a molecule that comprises a phosphorous thatis 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3)single-bonded to a heteroatom, and 4) single-bonded to anotherheteroatom, wherein each heteroatom can be the same or different. Theterms “phosphonate” and “phosphonate group” also include functionalgroups or moieties that comprise a phosphorous in the same oxidationstate as the phosphorous described above, as well as functional groupsor moieties that comprise a prodrug moiety that can separate from acompound so that the compound retains a phosphorous having thecharacteristics described above. For example, the terms “phosphonate”and “phosphonate group” include phosphonic acid, phosphonic monoester,phosphonic diester, phosphonamidate, and phosphonthioate functionalgroups. In one specific embodiment of the invention, the terms“phosphonate” and “phosphonate group” include functional groups ormoieties within a molecule that comprises a phosphorous that is 1)single-bonded to a carbon, 2) double-bonded to an oxygen, 3)single-bonded to an oxygen, and 4) single-bonded to another oxygen, aswell as functional groups or moieties that comprise a prodrug moietythat can separate from a compound so that the compound retains aphosphorous having such characteristics. In another specific embodimentof the invention, the terms “phosphonate” and “phosphonate group”include functional groups or moieties within a molecule that comprises aphosphorous that is 1) single-bonded to a carbon, 2) double-bonded to anoxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bondedto another oxygen or nitrogen, as well as functional groups or moietiesthat comprise a prodrug moiety that can separate from a compound so thatthe compound retains a phosphorous having such characteristics.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Prodrug moiety” refers to a labile functional group which separatesfrom the active anti-cancer compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with thephosphonate prodrug compounds of the invention include, but are notlimited to, amidases, esterases, microbial enzymes, phospholipases,cholinesterases, and phosphases. Prodrug moieties can serve to enhancesolubility, absorption and lipophilicity to optimize drug delivery,bioavailability and efficacy. A prodrug moiety may include an activemetabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂C(═O)R⁹ and acyloxymethyl carbonates—CH₂C(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC) —CH₂C(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al. (1992) J. Chem.Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal., U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof. Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of an hydrogen atom or an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfamic acids.Physiologically acceptable salts of a compound of an hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C—CH) and propargyl (—CH₂C≡CH),

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O,—NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)₂O⁻,—S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR,—P(═O)O₂RR—P(═O)(O⁻)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently —H, alkyl, aryl, heterocycle, protecting group or prodrugmoiety. Alkylene, alkenylene, and alkynylene groups may also besimilarly substituted.

“Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; Principlesof Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of theinvention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle,and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycleshave 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicycliccarbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system. Examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

“Linker” or “link” refers to a chemical moiety comprising a covalentbond or a chain or group of atoms that covalently attaches a phosphonategroup to a drug. Linkers include portions of substituents A¹ and A³,which include moieties such as: repeating units of alkyloxy (e.g.,polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.,polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotection. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) areclaims of “ether- or ester-forming groups”. Ether- or ester-forminggroups are capable of functioning as chemical protecting groups in thesynthetic schemes set forth herein. However, some hydroxyl and thioprotecting groups are neither ether-nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below. Such groups include by way of example and notlimitation, esters, amides, hydrazides, and the like.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

The phosphonate moieties of the compounds of the invention may or maynot be prodrug moieties, i.e. they may or may be susceptible tohydrolytic or enzymatic cleavage or modification. Certain phosphonatemoieties are stable under most or nearly all metabolic conditions. Forexample, a dialkylphosphonate, where the alkyl groups are two or morecarbons, may have appreciable stability in vivo due to a slow rate ofhydrolysis.

Within the context of phosphonate prodrug moieties, a large number ofstructurally-diverse prodrugs have been described for phosphonic acids(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)and are included within the scope of the present invention. An exemplaryphosphonate ester-forming group is the phenyl carbocycle in substructureA₃ having the formula:

-   -   wherein R₁ may be H or C₁-C₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7        or 8, and the phenyl carbocycle is substituted with 0 to 3 R₂        groups. Where Y₁ is O, a lactate ester is formed, and where Y₁        is N(R₂), N(OR₂) or N(N(R₂)₂, a phosphonamidate ester results.

In its ester-forming role, a protecting group typically is bound to anyacidic group such as, by way of example and not limitation, a —CO₂H or—C(S)OH group, thereby resulting in —CO₂R^(x) where R^(x) is definedherein. Also, R^(x) for example includes the enumerated ester groups ofWO 95/07920.

Examples of protecting groups include:

C₃-C₁₂ heterocycle (described above) or aryl. These aromatic groupsoptionally are polycyclic or monocyclic. Examples include phenyl,spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-,2-, 4- and 5-pyrimidinyl,

C₃-C₁₂ heterocycle or aryl substituted with halo, R¹, R¹—O—C₁-C₁₂alkylene, C₁-C₁₂ alkoxy, CN, NO₂, OH, carboxy, carboxyester, thiol,thioester, C₁-C₁₂ haloalkyl (1-6 halogen atoms), C₂-C₁₂ alkenyl orC₂-C₁₂ alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C₁-C₁₂alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-,3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl(including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and4-haloalkylphenyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms,C₁-C₁₂ alkyl including 4-trifluoromethylbenzyl and 2-, 3- and4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl),4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl,benzyl, alkylsalicylphenyl (C₁-C₄ alkyl, including 2-, 3- and4-ethylsalicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl(—C₁₀H₆—OH) and aryloxy ethyl [C₆-C₉ aryl (including phenoxy ethyl)],2,2′-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol,—C₆H₄—CH₂—N(CH₃)₂, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl(C₁₋₄ alkyl);

esters of 2-carboxyphenyl; and C₁-C₄ alkylene-C₃-C₆ aryl (includingbenzyl, —CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl, —CH₂-oxazolyl,—CH₂-isoxazolyl, —CH₂-thiazolyl, —CH₂-isothiazolyl, —CH₂-pyrazolyl,—CH₂-pyridinyl and —CH₂-pyrimidinyl) substituted in the aryl moiety by 3to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen,C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁-C₁₂haloalkyl (1 to 6 halogen atoms; including —CH₂CCl₃), C₁-C₁₂ alkyl(including methyl and ethyl), C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl; alkoxyethyl [C₁-C₆ alkyl including —CH₂—CH₂—O—CH₃ (methoxy ethyl)]; alkylsubstituted by any of the groups set forth above for aryl, in particularOH or by 1 to 3 halo atoms (including —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄—CH₃, —(CH₂)₅CH₃, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₃, and —CH₂CCl₃);

—N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catecholmonoester, —CH₂—C(O)—N(R¹)₂, —CH₂—S(O)(R¹), —CH₂—S(O)₂(R¹),—CH₂—CH(OC(O)CH₂R¹)—CH₂(OC(O)CH₂R¹), cholesteryl, enolpyruvate(HOOC—C(═CH₂)—), glycerol;

a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9monosaccharide residues);

triglycerides such as α-D-β-diglycerides (wherein the fatty acidscomposing glyceride lipids generally are naturally occurring saturatedor unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty acids such as linoleic,lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic andthe like fatty acids) linked to acyl of the parental compounds hereinthrough a glyceryl oxygen of the triglyceride;

phospholipids linked to the carboxyl group through the phosphate of thephospholipid;

phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo.(1974) 5(6):670-671;

cyclic carbonates such as (5-R_(d)-2-oxo-1,3-dioxolen-4-yl)methyl esters(Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where R_(d)is R₁, R₄ or aryl; and

The hydroxyl groups of the compounds of this invention optionally aresubstituted with one of groups III, IV or V disclosed in WO 94/21604, orwith isopropyl.

Table A lists examples of protecting group ester moieties that forexample can be bonded via oxygen to —C(O)O— and —P(O)(O—)₂ groups.Several amidates also are shown, which are bound directly to —C(O)— or—P(O)₂. Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesizedby reacting the compound herein having a free hydroxyl with thecorresponding halide (chloride or acyl chloride and the like) andN,N-dicyclohexyl-N-morpholine carboxamidine (or another base such asDBU, triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (orother solvent such as acetonitrile or N-methylpyrrolidone). When thecompound to be protected is a phosphonate, the esters of structures 5-7,11, 12, 21, and 23-26 are synthesized by reaction of the alcohol oralkoxide salt (or the corresponding amines in the case of compounds suchas 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate(or another activated phosphonate).

TABLE A 1. —CH₂—C(O)—N(R₁)₂* 2. —CH₂—S(O)(R₁) 3. —CH₂—S(O)₂(R₁) 4.—CH₂—O—C(O)—CH₂—C₆H₅ 5. 3-cholesteryl 6. 3-pyridyl 7. N-ethylmorpholino8. —CH₂—O—C(O)—C₆H₅ 9. —CH₂—O—C(O)—CH₂CH₃ 10. —CH₂—O—C(O)—C(CH₃)₃ 11.—CH₂—CCl₃ 12. —C₆H₅ 13. —NH—CH₂—C(O)O—CH₂CH₃ 14.—N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR₁ 16. —CH₂—O—C(O)—C₁₀H₁₅ 17.—CH₂—O—C(O)—CH(CH₃)₂ 18. —CH₂—C#H(OC(O)CH₂R₁)—CH₂—(OC(O)CH₂R₁)* 19.

20.

21.

22.

23.

24.

25.

26.

#-chiral center is (R), (S) or racemate.

Other esters that are suitable for use herein are described in EP632048.

Protecting groups also includes “double ester” formingprofunctionalities

such as —CH₂OC(O)OCH₃,

—CH₂SCOCH₃, —CH₂OCON(CH₃)₂, or alkyl- or aryl-acyloxyalkyl groups of thestructure —CH(R¹ or W⁵)O((CO)R³⁷) or —CH(R¹ or W⁵)((CO)OR³⁸) (linked tooxygen of the acidic group) wherein R³⁷ and R³⁸ are alkyl, aryl, oralkylaryl groups (see U.S. Pat. No. 4,968,788). Frequently R³⁷ and R³⁸are bulky groups such as branched alkyl, ortho-substituted aryl,meta-substituted aryl, or combinations thereof, including normal,secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example isthe pivaloyloxymethyl group. These are of particular use with prodrugsfor oral administration. Examples of such useful protecting groups arealkylacyloxymethyl esters and their derivatives, including—CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)C(CH₃)₃, —CH(CH₂OCH₃)OC(O)C(CH₃)₃,—CH(CH(CH₃)₂)OC(O)C(CH₃)₃, —CH₂OC(O)CH₂CH(CH₃)₂, —CH₂OC(O)C₆H₁₁,—CH₂OC(O)C₆H₅, —CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)CH₂CH₃, —CH₂OC(O)CH(CH₃)₂,—CH₂OC(O)C(CH₃)₃ and —CH₂OC(O)CH₂C₆H₅.

In some claims the protected acidic group is an ester of the acidicgroup and is the residue of a hydroxyl-containing functionality. Inother claims, an amino compound is used to protect the acidfunctionality. The residues of suitable hydroxyl or amino-containingfunctionalities are set forth above or are found in WO 95/07920. Ofparticular interest are the residues of amino acids, amino acid esters,polypeptides, or aryl alcohols. Typical amino acid, polypeptide andcarboxyl-esterified amino acid residues are described on pages 11-18 andrelated text of WO 95/07920 as groups L1 or L2. WO 95/07920 expresslyteaches the amidates of phosphonic acids, but it will be understood thatsuch amidates are formed with any of the acid groups set forth hereinand the amino acid residues set forth in WO 95/07920.

Typical esters for protecting acidic functionalities are also describedin WO 95/07920, again understanding that the same esters can be formedwith the acidic groups herein as with the phosphonate of the '920publication. Typical ester groups are defined at least on WO 95/07920pages 89-93 (under R³¹ or R³⁵), the table on page 105, and pages 21-23(as R). Of particular interest are esters of unsubstituted aryl such asphenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-and/or alkylestercarboxy-substituted aryl or alkylaryl, especiallyphenyl, ortho-ethoxyphenyl, or C₁-C₄ alkylestercarboxyphenyl (salicylateC₁-C₁₂ alkylesters).

The protected acidic groups, particularly when using the esters oramides of WO 95/07920, are useful as prodrugs for oral administration.However, it is not essential that the acidic group be protected in orderfor the compounds of this invention to be effectively administered bythe oral route. When the compounds of the invention having protectedgroups, in particular amino acid amidates or substituted andunsubstituted aryl esters are administered systemically or orally theyare capable of hydrolytic cleavage in vivo to yield the free acid.

One or more of the acidic hydroxyls are protected. If more than oneacidic hydroxyl is protected then the same or a different protectinggroup is employed, e.g., the esters may be different or the same, or amixed amidate and ester may be used.

Typical hydroxy protecting groups described in Greene (pages 14-118)include substituted methyl and alkyl ethers, substituted benzyl ethers,silyl ethers, esters including sulfonic acid esters, and carbonates. Forexample:

-   -   Ethers (methyl, t-butyl, allyl);    -   Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,        t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl,        Benzyloxymethyl, p-Methoxybenzyloxymethyl,        (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl,        4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl,        2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,        2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl,        3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,        1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,        4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl        S,S-Dioxido,        1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,        1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,        2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));    -   Substituted Ethyl Ethers (1-Ethoxyethyl,        1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,        1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,        2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,        2-(Phenylselenyl)ethyl,    -   p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);    -   Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl,        o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl,        p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl,        3-Methyl-2-picolyl N-Oxido, Diphenylmethyl,        p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl,        α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,        Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,        4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,        4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,        4,4′,4″-Tris(levulinoyloxyphenyl)methyl,        4,4′,4″-Tris(benzoyloxyphenyl)methyl,        3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,        1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,        9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,        1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido);    -   Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,        Dimethylisopropylsilyl, Diethylisopropylsilyl,        Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl,        Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,        Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl);    -   Esters (Formate, Benzoylformate, Acetate, Choroacetate,        Dichloroacetate, Trichloroacetate, Trifluoroacetate,        Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,        p-Chlorophenoxyacetate, p-poly-Phenylacetate,        3-Phenylpropionate, 4-Oxopentanoate (Levulinate),        4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,        Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,        2,4,6-Trimethylbenzoate (Mesitoate));    -   Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,        2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,        2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,        Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl,        3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl        Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate);    -   Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,        4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,        2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,        4-(Methylthiomethoxy)butyrate,        2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters        (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3        tetramethylbutyl)phenoxyacetate,        2,4-Bis(1,1-dimethylpropyl)phenoxyacetate,        Chlorodiphenylacetate, Isobutyrate, Monosuccinate,        (E)-2-Methyl-2-butenoate (Tigloate),        o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate,        Nitrate, Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate,        N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,        2,4-Dinitrophenylsulfenate); and    -   Sulfonates (Sulfate, Methanesulfonate (Mesylate),        Benzylsulfonate, Tosylate).

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the protecting functionality) are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableB, still more typically, epoxides, acetonides, cyclic ketals and arylacetals.

TABLE B

wherein R⁹ is C₁-C₆ alkyl.

Amino Protecting Groups

Another set of protecting groups include any of the typical aminoprotecting groups described by Greene at pages 315-385. They include:

-   -   Carbamates: (methyl and ethyl, 9-fluorenylmethyl,        9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,        2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,        4-methoxyphenacyl);    -   Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl,        2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,        1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,        1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenyl        yl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and        4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,        1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,        4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,        benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,        p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,        9-anthrylmethyl, diphenylmethyl);    -   Groups With Assisted Cleavage: (2-methylthioethyl,        2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,        [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,        2,4-dimethylthiophenyl, 2-phosphonioethyl,        2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,        m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);    -   Groups Capable of Photolytic Cleavage: (m-nitrophenyl,        3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives        (phenothiazinyl-(10)-carbonyl,        N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);    -   Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate,        p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,        cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,        2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,        2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,        p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,        1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,        2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,        2,4,6-trimethylbenzyl);    -   Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl,        N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,        N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl,        N-benzoyl, N-p-phenylbenzoyl);    -   Amides With Assisted Cleavage: (N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl,        (N′-dithiobenzyloxycarbonylamino)acetyl,        N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl,        N-acetylmethionine, N-o-nitrobenzoyl,        N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);    -   Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl,        N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,        N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,        5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,        5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one,        1-substituted 3,5-dinitro-4-pyridonyl);    -   N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl,        N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,        N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary        Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,        N-5-dibenzosuberyl, N-triphenylmethyl,        N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,        N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,        N-2-picolylamine N-oxide);    -   Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene,        N-p-methoxybenzylidene, N-diphenylmethylene,        N-[(2-pyridyl)mesityl]methylene, N,(N′,N-dimethylaminomethylene,        N,N-isopropylidene, N-p-nitrobenzylidene, N-salicylidene,        N-5-chlorosalicylidene,        N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);    -   Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));    -   N-Metal Derivatives (N-borane derivatives, N-diphenylborinic        acid derivatives, N-[phenyl(pentacarbonylchromium- or        -tungsten)]carbenzyl, N-copper or N-zinc chelate);    -   N—N Derivatives: (N-nitro, N-nitroso, N-oxide);    -   N—P Derivatives: (N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl        phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl);    -   N—Si Derivatives, N—S Derivatives, and N-Sulfenyl Derivatives:        (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,        N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,        N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives        (N-p-toluenesulfonyl, N-benzenesulfonyl,        N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,        N-2,4,6-trimethoxybenzenesulfonyl,        N-2,6-dimethyl-4-methoxybenzenesulfonyl,        N-pentamethylbenzenesulfonyl,        N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,        N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-2,6-dimethoxy-4-methylbenzenesulfonyl,        N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,        N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,        N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl,        N-benzylsulfonyl, N-trifluoromethylsulfonyl,        N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, —NHC(O)R¹ or —N—CR¹N(R¹)₂. Another protectinggroup, also useful as a prodrug for amino or —NH(R⁵), is:

See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.

Amino Acid and Polypeptide Protecting Group and Conjugates

An amino acid or polypeptide protecting group of a compound of theinvention has the structure R¹⁵NHCH(R¹⁶)C(O)—, where R¹⁵ is H, an aminoacid or polypeptide residue, or R⁵, and R¹⁶ is defined below.

R¹⁶ is lower alkyl or lower alkyl (C₁-C₆) substituted with amino,carboxyl, amide, carboxyl ester, hydroxyl, C₆-C₇ aryl, guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R¹⁰also is taken together with the amino acid αN to form a proline residue(R¹⁰=—CH₂)₃—). However, R¹⁰ is generally the side group of anaturally-occurring amino acid such as H, —CH₃, —CH(CH₃)₂,—CH₂—CH(CH₃)₂, —CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH,—CH(OH)—CH₃, —CH₂—SH, —CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂,—CH₂—COOH, —CH₂—CH₂—COOH, —(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R₁₀also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another set of protecting groups include the residue of anamino-containing compound, in particular an amino acid, a polypeptide, aprotecting group, —NHSO₂R, NHC(O)R, —N(R)₂, NH₂ or —NH(R)(H), wherebyfor example a carboxylic acid is reacted, i.e. coupled, with the amineto form an amide, as in C(O)NR₂. A phosphonic acid may be reacted withthe amine to form a phosphonamidate, as in —P(O)(OR)(NR₂).

In general, amino acids have the structure R¹⁷C(O)CH(R¹⁶)NH—, where R¹⁷is —OH, —OR, an amino acid or a polypeptide residue. Amino acids are lowmolecular weight compounds, on the order of less than about 1000 MW andwhich contain at least one amino or imino group and at least onecarboxyl group. Generally the amino acids will be found in nature, i.e.,can be detected in biological material such as bacteria or othermicrobes, plants, animals or man. Suitable amino acids typically arealpha amino acids, i.e. compounds characterized by one amino or iminonitrogen atom separated from the carbon atom of one carboxyl group by asingle substituted or unsubstituted alpha carbon atom. Of particularinterest are hydrophobic residues such as mono- or di-alkyl or arylamino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the parental drug. Typically, the residue does not contain asulfhydryl or guanidino substituent.

Naturally-occurring amino acid residues are those residues foundnaturally in plants, animals or microbes, especially proteins thereof.Polypeptides most typically will be substantially composed of suchnaturally-occurring amino acid residues. These amino acids are glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, glutamic acid, aspartic acid, lysine, hydroxylysine,arginine, histidine, phenylalanine, tyrosine, tryptophan, proline,asparagine, glutamine and hydroxyproline. Additionally, unnatural aminoacids, for example, valanine, phenylglycine and homoarginine are alsoincluded. Commonly encountered amino acids that are not gene-encoded mayalso be used in the present invention. All of the amino acids used inthe present invention may be either the D- or L-optical isomer. Inaddition, other peptidomimetics are also useful in the presentinvention. For a general review, see Spatola, A. F., in Chemistry andBiochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983).

When protecting groups are single amino acid residues or polypeptidesthey optionally are substituted at R³ of substituents A¹, A² or A³ inFormula I. These conjugates are produced by forming an amide bondbetween a carboxyl group of the amino acid (or C-terminal amino acid ofa polypeptide for example). Similarly, conjugates are formed between R³(Formula I) and an amino group of an amino acid or polypeptide.Generally, only one of any site in the parental molecule is amidatedwith an amino acid as described herein, although it is within the scopeof this invention to introduce amino acids at more than one permittedsite. Usually, a carboxyl group of R³ is amidated with an amino acid. Ingeneral, the α-amino or α-carboxyl group of the amino acid or theterminal amino or carboxyl group of a polypeptide are bonded to theparental functionalities, i.e., carboxyl or amino groups in the aminoacid side chains generally are not used to form the amide bonds with theparental compound (although these groups may need to be protected duringsynthesis of the conjugates as described further below).

With respect to the carboxyl-containing side chains of amino acids orpolypeptides it will be understood that the carboxyl group optionallywill be blocked, e.g., by R¹, esterified with R⁵ or amidated. Similarly,the amino side chains R¹⁶ optionally will be blocked with R¹ orsubstituted with R⁵.

Such ester or amide bonds with side chain amino or carboxyl groups, likethe esters or amides with the parental molecule, optionally arehydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10)conditions. Alternatively, they are substantially stable in thegastrointestinal tract of humans but are hydrolyzed enzymatically inblood or in intracellular environments. The esters or amino acid orpolypeptide amidates also are useful as intermediates for thepreparation of the parental molecule containing free amino or carboxylgroups. The free acid or base of the parental compound, for example, isreadily formed from the esters or amino acid or polypeptide conjugatesof this invention by conventional hydrolysis procedures.

When an amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used. In general, if the intermediates are tobe hydrolyzed non-enzymatically (as would be the case where the amidesare used as chemical intermediates for the free acids or free amines), Disomers are useful. On the other hand, L isomers are more versatilesince they can be susceptible to both non-enzymatic and enzymatichydrolysis, and are more efficiently transported by amino acid ordipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R^(x)or R^(y) include the following:

Glycine;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid;

Amino acid amides such as glutamine and asparagine;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;

Other basic amino acid residues such as histidine;

Diaminodicarboxylic acids such as α,α′-diaminosuccinic acid,α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid, α,α′-diaminopimelicacid, α,α′-diamino-β-hydroxypimelic acid, α,α′-diaminosuberic acid,α,α′-diaminoazelaic acid, and α,α′-diaminosebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline,γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, andazetidine-2-carboxylic acid;

A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino acid suchas alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-a-methyl-y-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues;canavine and canaline; γ-hydroxyornithine;

2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminicacid;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine;

Other sulfur containing amino acid residues including cysteine;homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteinesulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-,2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophananalogues and derivatives including kynurenine, 3-hydroxykynurenine,2-hydroxytryptophan and 4-carboxytryptophan;

α-Amino substituted amino acids including sarcosine (N-methylglycine),N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acids including serine,threonine, allothreonine, phosphoserine and phosphothreonine.

Polypeptides are polymers of amino acids in which a carboxyl group ofone amino acid monomer is bonded to an amino or imino group of the nextamino acid monomer by an amide bond. Polypeptides include dipeptides,low molecular weight polypeptides (about 1500-5000 MW) and proteins.Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, andsuitably are substantially sequence-homologous with human, animal, plantor microbial proteins. They include enzymes (e.g., hydrogen peroxidase)as well as immunogens such as KLH, or antibodies or proteins of any typeagainst which one wishes to raise an immune response. The nature andidentity of the polypeptide may vary widely.

The polypeptide amidates are useful as immunogens in raising antibodiesagainst either the polypeptide (if it is not immunogenic in the animalto which it is administered) or against the epitopes on the remainder ofthe compound of this invention.

Antibodies capable of binding to the parental non-peptidyl compound areused to separate the parental compound from mixtures, for example indiagnosis or manufacturing of the parental compound. The conjugates ofparental compound and polypeptide generally are more immunogenic thanthe polypeptides in closely homologous animals, and therefore make thepolypeptide more immunogenic for facilitating raising antibodies againstit. Accordingly, the polypeptide or protein may not need to beimmunogenic in an animal typically used to raise antibodies, e.g.,rabbit, mouse, horse, or rat, but the final product conjugate should beimmunogenic in at least one of such animals. The polypeptide optionallycontains a peptidolytic enzyme cleavage site at the peptide bond betweenthe first and second residues adjacent to the acidic heteroatom. Suchcleavage sites are flanked by enzymatic recognition structures, e.g., aparticular sequence of residues recognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus or carbon atoms of the compounds herein. In claims where W₁is phosphonate it is expected that this peptide will be cleaved by theappropriate peptidolytic enzyme, leaving the carboxyl of the proximalamino acid residue to autocatalytically cleave the phosphonoamidatebond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NR, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When aphosphonate is to be protected, the sequence —X⁴-pro-X⁵— (where X⁴ isany amino acid residue and X⁵ is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X⁴ with a free carboxyl, which in turn is expected toautocatalytically cleave the phosphonoamidate bond. The carboxy group ofX⁵ optionally is esterified with benzyl.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., (1992) Pharm Res. 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of the amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in the amidate compounds of this invention. Amino acids in theD configuration can be used to reduce the susceptibility of a di- ortripeptide to hydrolysis by proteases common to the brush border such asaminopeptidase N. In addition, di- or tripeptides alternatively areselected on the basis of their relative resistance to hydrolysis byproteases found in the lumen of the intestine. For example, tripeptidesor polypeptides lacking asp and/or glu are poor substrates foraminopeptidase A, di- or tripeptides lacking amino acid residues on theN-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) arepoor substrates for endopeptidase, and peptides lacking a pro residue atthe penultimate position at a free carboxyl terminus are poor substratesfor carboxypeptidase P. Similar considerations can also be applied tothe selection of peptides that are either relatively resistant orrelatively susceptible to hydrolysis by cytosolic, renal, hepatic, serumor other peptidases. Such poorly cleaved polypeptide amidates areimmunogens or are useful for bonding to proteins in order to prepareimmunogens.

SPECIFIC EMBODIMENTS OF THE INVENTION

Specific values described for radicals, substituents, and ranges, aswell as specific embodiments of the invention described herein, are forillustration only; they do not exclude other defined values or othervalues within defined ranges.

In one specific embodiment of the invention, the conjugate is a compoundthat is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

A⁰ is A¹, A² or W³;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(1b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

and W^(5a) is a carbocycle or a heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups. A specific value forM12a is 1.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In another specific embodiment of the invention e M12b is 0, Y² is abond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally andindependently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention A² is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is optionallyand independently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention M12a is 1.

In another specific embodiment of the invention A² is selected fromphenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl andsubstituted pyridyl.

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In a specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is a carbocycle.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is phenyl.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R¹ is H.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R¹);and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In a specific embodiment of the invention A⁰ is of the formula:

wherein each R is independently (C₁-C₆)alkyl.

In a specific embodiment of the invention R^(x) is independently H, R¹,W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2c) is O, N(R^(y)) or S.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2d) is O or N(R^(y)).

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(y) is hydrogen or alkyl of1 to 10 carbons.

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention Y¹ is O or S

In a specific embodiment of the invention Y² is O, N(R^(y)) or S.

In one specific embodiment of the invention R^(x) is a group of theformula:

wherein:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R^(y) is H, W³, R² or a protecting group;

provided that:

if m1a, m12c, and m1d are 0, then m1b, m1c and m1e are 0;

if m1a and m12c are 0 and m1d is not 0, then m1b and m1c are 0;

if m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1cand m/e are 0;

if m1a is 0 and m12c and m1d are not 0, then m1b is 0;

if m12c and m1d are 0 and m1a is not 0, then at least two of m1b, m1cand m1e are 0;

if m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1care 0; and

if m1d is 0 and m1a and m12c are not 0, then at least one of m1c and m1eare 0.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-601:

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the compound includes at leastone A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(X))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3h) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵,

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula 1-336:

or a pharmaceutically acceptable salt thereof wherein:

A⁰ is A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a), is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

3. A compound of any one of formulae 1-336 wherein:

A⁰ is A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-[L-P(═Y¹)—Y²—R^(x)]_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of 500-601;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(X)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

M2 is 1, 2, or 3;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

nn is 1, 2, or 3; and

L is a linking group.

In another specific embodiment, the invention provides a compound ofwhich is a compound of the formula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-601;

nn is 1, 2, or 3;

A⁰ is A¹, A², or W³ with the proviso that the compound includes at leastone A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)),

—OC(Y¹)R^(x), —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),—SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),—N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In compounds of the invention W⁵ carbocycles and W⁵ heterocycles may beindependently substituted with 0 to 3 R² groups. W⁵ may be a saturated,unsaturated or aromatic ring comprising a mono- or bicyclic carbocycleor heterocycle. W⁵ may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.The W⁵ rings are saturated when containing 3 ring atoms, saturated ormono-unsaturated when containing 4 ring atoms, saturated, or mono- ordi-unsaturated when containing 5 ring atoms, and saturated, mono- ordi-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R² groups, as defined above. For example, substituted W⁵carbocycles include:

Examples of substituted phenyl carbocycles include:

Conjugates of Formula I

In one embodiment, the invention provides a conjugate of Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

X is selected from O, C(R^(y))₂, C═C(R^(y))₂, NR and S;

Z¹ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F,Cl, Br, and I;

Z² is selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, and C₁-C₈ substitutedalkynyl,

Y¹ is independently O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or N—NR₂;

Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),N—NR₂, S, S—S, S(O), or S(O)₂;

M2 is 0, 1 or 2;

R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, aprotecting group (PG), or W³; or when taken together, R^(y) forms acarbocyclic ring of 3 to 7 carbon atoms;

R^(x) is independently R^(y), a protecting group, or the formula:

wherein:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or—SO₂W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ isindependently substituted with 0 to 3 R^(y) groups.

For a conjugate of Formula I, in one specific embodiment, C₁-C₈substituted alkyl, C₁-C₈ substituted alkenyl, C₁-C₈ substituted alkynyl,C₆-C₂₀ substituted aryl, and C₂-C₂₀ substituted heterocycle areindependently substituted with one or more substituents selected from F,Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₃-C₁₂ carbocycle, C₆-C₂₀ aryl, C₂-C₂₀ heterocycle,polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

For a conjugate of Formula I, in one specific embodiment, “protectinggroup” is selected from a carboxyl ester, a carboxamide, an aryl ether,an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, acarbonate, and a carbamate.

For a conjugate of Formula I, in one specific embodiment, W⁵ is selectedfrom the structures:

For a conjugate of Formula I, in one specific embodiment, X is O andR^(y) is H.

For a conjugate of Formula I, in one specific embodiment, X is C═CH₂ andR^(y) is H.

For a conjugate of Formula I, in one specific embodiment, Z¹ is OH.

For a conjugate of Formula I, in one specific embodiment, Z² is C₁-C₈alkyl or C₁-C₈ substituted alkyl.

For a conjugate of Formula I, in one specific embodiment, Z² is CH₃.

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

wherein, in a more specific embodiment, Z¹ is OH; Z² is C₁-C₈ alkyl orC₁-C₈ substituted alkyl; and Z² is CH₃.

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

wherein R² is H or C₁-C₈ alkyl.

In one specific embodiment, the conjugate of formula I has the followingformula:

In one specific embodiment, the conjugate of formula I has the followingformula:

wherein Y^(2c) is O, N(R^(y)) or S.

In one specific embodiment, the conjugate of formula I has the followingformula:

wherein, in a more specific embodiment, Y^(2c) is O; Y^(2c) is N(CH₃);and R^(y) is H or C₁-C₈ alkyl.

For a conjugate of Formula I, in one specific embodiment, thesubstituted triazole has the structure:

In one specific embodiment, the conjugate of Formula I is a conjugate ofthe following formula:

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

Z¹ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F,Cl, Br, and I;

Z² is selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, and C₁-C₈ substitutedalkynyl,

R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, aprotecting group (PG), or W³; or when taken together, R^(y) forms acarbocyclic ring of 3 to 7 carbon atoms;

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or—SO₂W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ isindependently substituted with 0 to 3 R^(y) groups.

In one specific embodiment, the conjugate of Formula I has the followingformula:

wherein PG is a protecting group selected from an ether-forming group, athioether-forming group, an ester-forming group, a thioester-forminggroup, a silyl-ether forming group, an amide-forming group, anacetal-forming group, a ketal-forming group, a carbonate-forming group,a carbamate-forming group, a urea-forming group, an amino acidconjugate, and a polypeptide conjugate.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof; wherein B isadenine, guanine, cytosine, uracil, thymine, 7-deazaadenine,7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine,nebularine, nitropyrrole, nitroindole, 2-aminopurine,2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine,pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine,isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine,4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine,O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole,substituted triazole, or pyrazolo[3,4-D]pyrimidine. In an additionalembodiment, the compound is isolated and purified.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof; wherein B isadenine, guanine, cytosine, uracil, thymine, 7-deazaadenine,2,6-diaminopurine, 5-fluorocytosine, or c-propyl-2,6-diaminopurine. Inan additional embodiment, the compound is isolated and purified.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof. In anadditional embodiment, the compound is isolated and purified.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof, wherein B isadenine, guanine, cytosine, uracil, thymine, 7-deazaadenine,7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine,nebularine, nitropyrrole, nitroindole, 2-aminopurine,2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine,pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine,isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine,4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine,O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole,substituted triazole, or pyrazolo[3,4-D]pyrimidine. In an additionalembodiment, the compound is isolated and purified.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof; wherein B isadenine, guanine, cytosine, uracil, thymine, 7-deazaadenine,2,6-diaminopurine, 5-fluorocytosine, or c-propyl-2,6-diaminopurine. Inan additional embodiment, the compound is isolated and purified.

In one specific embodiment, the invention provides a conjugate ofFormula I having one of the following formulae:

or a pharmaceutically acceptable salt or solvate thereof. In anadditional embodiment, the compound is isolated and purified.

Conjugates of Formula II

In one embodiment, the invention provides a conjugate of Formula II:

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

X is selected from O, C(R^(y))₂, OC(R^(y))₂, NR and S;

Z¹ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F,Cl, Br, and I;

Z² is selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, and C₁-C₈ substitutedalkynyl,

Y¹ is independently O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or N—NR₂;

Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),N—NR₂, S, S—S, S(O), or S(O)₂;

M2 is 0, 1 or 2;

R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, aprotecting group, or W³; or when taken together, R^(y) forms acarbocyclic ring of 3 to 7 carbon atoms;

R^(x) is independently R^(y), a protecting group, or the formula:

wherein:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or—SO₂W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ isindependently substituted with 0 to 3 R^(y) groups.

For a conjugate of Formula II, in one specific embodiment, C₁-C₈substituted alkyl, C₁-C₈ substituted alkenyl, C₁-C₈ substituted alkynyl,C₆-C₂₀ substituted aryl, and C₂-C₂₀ substituted heterocycle areindependently substituted with one or more substituents selected from F,Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₃-C₁₂ carbocycle, C₆-C₂₀ aryl, C₂-C₂₀ heterocycle,polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

For a conjugate of Formula II, in one specific embodiment, “protectinggroup” is selected from a carboxyl ester, a carboxamide, an aryl ether,an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, acarbonate, and a carbamate.

For a conjugate of Formula II, in one specific embodiment, W⁵ isselected from the structures:

For a conjugate of Formula II, in one specific embodiment, X is O andR^(y) is H.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein, in a more specific embodiment, Z¹ is OH; and Z² is CH₃.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein, in a more specific embodiment, Z² is C₁-C₈ alkyl or C₁-C₈substituted alkyl.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein R² is H or C₁-C₈ alkyl.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein Y^(2c) is O, N(R^(y)) or S.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein, in a more specific embodiment, Y^(2c) is O; Y^(2c) is N(CH₃).

In one specific embodiment, the substituted triazole has the structure:

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

X^(a) is selected from O, NR and S;

Z¹ is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F,Cl, Br, and I;

Z² is selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, and C₁-C₈ substitutedalkynyl,

R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, aprotecting group, or W³; or when taken together, R^(y) forms acarbocyclic ring of 3 to 7 carbon atoms;

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or—SO₂W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ isindependently substituted with 0 to 3 R^(y) groups.

In one specific embodiment, the conjugate of Formula II has thefollowing formula:

wherein PG is a protecting group selected from an ether-forming group, athioether-forming group, an ester-forming group, a thioester-forminggroup, a silyl-ether forming group, an amide-forming group, anacetal-forming group, a ketal-forming group, a carbonate-forming group,a carbamate-forming group, a urea-forming group, an amino acidconjugate, and an olypeptide conjugate

Conjugates of Formula III

In one embodiment, the invention provides a conjugate of Formula III:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

X is selected from O, C(R^(y))₂, OC(R^(y))₂, NR and S;

Z is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl,Br, and I;

Y¹ is independently O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or N—NR₂;

Y² is independently O, CR², NR, N(O)(R), N(OR), ⁺(O)(OR), N—NR₂, S, S—S,S(O), or S(O)₂;

M2 is 0, 1 or 2;

R^(y) is independently H, F, Cl, Br, I, OH, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, or W 3; orwhen taken together, R^(y) forms a carbocyclic ring of 3 to 7 carbonatoms;

R^(x) is independently R^(y), a protecting group, or the formula:

wherein:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or—SO₂W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ isindependently substituted with 0 to 3 R^(y) groups.

For a conjugate of Formula II, in one specific embodiment, C₁-C₈substituted alkyl, C₁-C₈ substituted alkenyl, C₁-C₈ substituted alkynyl,C₆-C₂₀ substituted aryl, and C₂-C₂₀ substituted heterocycle areindependently substituted with one or more substituents selected from F,Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₃-C₁₂ carbocycle, C₆-C₂₀ aryl, C₂-C₂₀ heterocycle,polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

For a conjugate of Formula II, in one specific embodiment, “protectinggroup” is selected from a carboxyl ester, a carboxamide, an aryl ether,an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, acarbonate, and a carbamate.

In one specific embodiment, for a conjugate of Formula III, W⁵ isselected from the structures:

In one specific embodiment, for a conjugate of Formula III, X is O andeach R^(y) is H.

In one specific embodiment, the conjugate of Formula III is a resolvedenantiomer having the structure:

In one specific embodiment, the conjugate of Formula III is a resolvedenantiomer having the structure:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

wherein R² is H or C₁-C₈ alkyl.

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

wherein in a more specific embodiment, Z is H and B is adenine.

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

wherein Y^(2c) is O, N(R^(y)) or S.

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

wherein, in a more specific embodiment, Y^(2c) is O or N(CH₃).

In one specific embodiment, for a conjugate of Formula III, substitutedtriazole has the structure:

In one specific embodiment, the conjugate of Formula III has thefollowing formula:

wherein:

B is selected from adenine, guanine, cytosine, uracil, thymine,7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole,2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine,pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine,isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine,6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine,N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine,5,6-dihydrouracil, 4-methylindole, substituted triazole, andpyrazolo[3,4-D]pyrimidine;

X is selected from O, C(R^(y))₂, OC(R^(y))₂, NR and S;

Z is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl,Br, and I;

Y² is independently O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), N—NR₂, S,S—S, S(O), or S(O)₂;

R^(y) is independently H, F, Cl, Br, I, OH, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—SO₂R), arylsulfone(—SO₂Ar), arylsulfoxide (—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂),alkylsulfoxide (—SOR), ester (—C(═O)OR), amido (—C(═O)NR₂), 5-7 memberedring lactam, 5-7 membered ring lactone, nitrile (—CN), azido (—N₃),nitro (—NO₂), C₁-C₈ alkoxy (—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, or W³; orwhen taken together, R^(y) forms a carbocyclic ring of 3 to 7 carbonatoms;

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substitutedheterocycle, or a protecting group; and

PG is a protecting group selected from an ether-forming group, anester-forming group, a silyl-ether forming group, an amide-forminggroup, an acetal-forming group, a ketal-forming group, acarbonate-forming group, a carbamate-forming group, an amino acid, and apolypeptide.

Linking Groups and Linkers

The invention provides conjugates that comprise an anti-cancer compoundthat is linked to one or more phosphonate groups either directly (e.g.through a covalent bond) or through a linking group (i.e. a linker). Thenature of the linker is not critical provided it does not interfere withthe ability of the phosphonate containing compound to function as atherapeutic agent. The phosphonate or the linker can be linked to thecompound (e.g. a compound of Formula 500-601) at any syntheticallyfeasible position on the compound by removing a hydrogen or any portionof the compound to provide an open valence for attachment of thephosphonate or the linker.

In one embodiment of the invention the linking group or linker (whichcan be designated “L”) can include all or a portions of the group A⁰,A¹, A², or W³ described herein.

In another embodiment of the invention the linking group or linker has amolecular weight of from about 20 daltons to about 400 daltons.

In another embodiment of the invention the linking group or linker has alength of about 5 angstroms to about 300 angstroms.

In another embodiment of the invention the linking group or linkerseparates the DRUG and a P(═Y¹) residue by about 5 angstroms to about200 angstroms, inclusive, in length.

In another embodiment of the invention the linking group or linker is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2,3, or 4) of the carbon atoms is optionally replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

In another embodiment of the invention the linking group or linker is ofthe formula W-A wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl or a combinationthereof, wherein W is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker is adivalent radical formed from a peptide.

In another embodiment of the invention the linking group or linker is adivalent radical formed from an amino acid.

In another embodiment of the invention the linking group or linker is adivalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is ofthe formula W—(CH₂)_(n) wherein, n is between about 1 and about 10; andW is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—,—S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker ismethylene, ethylene, or propylene.

In another embodiment of the invention the linking group or linker isattached to the phosphonate group through a carbon atom of the linker.

Intracellular Targeting

The phosphonate group of the compounds of the invention may cleave invivo in stages after they have reached the desired site of action, i.e.inside a cell. One mechanism of action inside a cell may entail a firstcleavage, e.g. by esterase, to provide a negatively-charged “locked-in”intermediate. Cleavage of a terminal ester grouping in a compound of theinvention thus affords an unstable intermediate which releases anegatively charged “locked in” intermediate.

After passage inside a cell, intracellular enzymatic cleavage ormodification of the phosphonate or prodrug compound may result in anintracellular accumulation of the cleaved or modified compound by a“trapping” mechanism. The cleaved or modified compound may then be“locked-in” the cell by a significant change in charge, polarity, orother physical property change which decreases the rate at which thecleaved or modified compound can exit the cell, relative to the rate atwhich it entered as the phosphonate prodrug. Other mechanisms by which atherapeutic effect are achieved may be operative as well. Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphatases.

In selected instances in which the drug is of the nucleoside type, suchas is the case of zidovudine and numerous other antiretroviral agents,it is known that the drug is activated in vivo by phosphorylation. Suchactivation may occur in the present system by enzymatic conversion ofthe “locked-in” intermediate with phosphokinase to the activephosphonate diphosphate and/or by phosphorylation of the drug itselfafter its release from the “locked-in” intermediate as described above.In either case, the original nucleoside-type drug will be convened, viathe derivatives of this invention, to the active phosphorylated species.

From the foregoing, it will be apparent that many different drugs can bederivatized in accord with the present invention. Numerous such drugsare specifically mentioned herein. However, it should be understood thatthe discussion of drug families and their specific members forderivatization according to this invention is not intended to beexhaustive, but merely illustrative.

Anti-Cancer Compounds

The compounds of the invention include those with anti-cancer activity.In particular, the compounds include anti-cancer compounds. Thecompounds of the inventions bear one or more (e.g. 1, 2, 3, or 4)phosphonate groups, which may be a prodrug moiety.

Typically, compounds of the invention have a molecular weight of fromabout 400 amu to about 10,000 amu; in a specific embodiment of theinvention, compounds have a molecular weight of less than about 5000amu; in another specific embodiment of the invention, compounds have amolecular weight of less than about 2500 amu; in another specificembodiment of the invention, compounds have a molecular weight of lessthan about 1000 amu; in another specific embodiment of the invention,compounds have a molecular weight of less than about 800 amu; in anotherspecific embodiment of the invention, compounds have a molecular weightof less than about 600 amu; and in another specific embodiment of theinvention, compounds have a molecular weight of less than about 600 amuand a molecular weight of greater than about 400 amu.

The compounds of the invention also typically have a logD(polarity) lessthan about 5. In one embodiment the invention provides compounds havinga logD less than about 4; in another one embodiment the inventionprovides compounds having a logD less than about 3; in another oneembodiment the invention provides compounds having a logD greater thanabout −5; in another one embodiment the invention provides compoundshaving a logD greater than about −3; and in another one embodiment theinvention provides compounds having a logD greater than about 0 and lessthan about 3.

In one specific embodiment the invention provides compounds that mayfall within the generic definition of the term anti-cancer compound butwhich further comprise a phosphonate group, e.g., a phosphonate diester,phosphonamidate-ester prodrug, or a phosphondiamidate-ester (Jiang etal., US 2002/0173490 A1).

Selected substituents within the compounds of the invention are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. For example, R^(x) contains a R^(y)substituent. R¹ can be R², which in turn can be R³. If R³ is selected tobe R^(3c), then a second instance of R^(x) can be selected. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³, R^(y) and R³ are all recursivesubstituents in certain claims. Typically, each of these mayindependently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, 2, 1, or 0, times in a given claim. More typically, each ofthese may independently occur 12 or fewer times in a given claim. Moretypically yet, W³ will occur 0 to 8 times, R^(y) will occur 0 to 6 timesand R³ will occur 0 to 10 times in a given claim. Even more typically,W³ will occur 0 to 6 times, R^(y) will occur 0 to 4 times and R³ willoccur 0 to 8 times in a given claim.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an claim of the invention, the total numberwill be determined as set forth above.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “R^(6a)” then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines indicate the site ofcovalent bond attachments to the adjoining groups, moieties, or atoms.

The term “anti-cancer compound” includes not only the genericdisclosures cited above but also each and every species set forththerein. The phosphonate group may be a phosphonate prodrug moiety. Theprodrug moiety may be sensitive to hydrolysis, such as, but not limitedto, a pivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

The term “anti-cancer compound” also includes gefitinib, imatinib,erlotinib, vatalanib, fosteabine, camptosar, irinotecan, hycamtin,femara, letrozole, fadrozole, temozolomide, etopophos, anastrozole,arimidex, carboplatin, paraplatin, exemestane, atamestane, epirubicin,adriamycin, taxotere, taxol, vinorelbine, ospemifene, troglitazone,etoposide, everolimus, vincristine, sirolimus, raltitrexed (tomudex),aminopterin, alvocidib, bortezomib, VX-148, vinblastine, tipifarnib,mitoxantrone, vindesine, lonafarib, merimepodib, brequinar, amsacrine,CEP-701, decitabine, teniposide, midostaurin, MLN-518, PD-184352,emetrexed (ALIMTA), 10-propargyl-10-deaza-aminopterin (PDX),tacedinaline, thalidomide, TLK-286, pixantrone, pentostatin,enocitabine, clofarabine, BCX-1777, rubitecan, suberanilohydroxamicacid, revimid, MS-275, dexamethasone, LAQ-824, fludarabine, pirarubicin,teriflunomide, cerubidin HCL, idarubicin HCL, exatecan, sardomozide,adriamycin, methopterin, mizoribine, tamoxifen citrate/toremifinecitrate, raloxifene hydrochloride, mycophenolate, dexamethasone,methotrexate, GLEEVEC, PNP-405, MDL-74428,9-(3,3-dimethyl-5-phosphonopentyl) guanine, DADMe-IMMG, camptosar,idarubicin, leflunomide, BAY-43-9006, bicyclo nucleobase compounds,2-fluoro, 2′, 3′ didehydro, 4′ phosphonate nucleoside compounds,gemcitabine, cladribine, rofecoxib, ANA-245, and halobetasol propionate.

In one embodiment of the invention, the compound is not a kinaseinhibitor, an IMPDH, a PMP, an anti-viral agent, or an autoimmune systemenhancer. In another embodiment of the invention, the compound is not acompound of formula 501, 519, 597, 541, 518, 558, 591, 593, 592, 503,504, 505, 506, 542, 544, 545, 546, 516, or 512.

Cellular Accumulation

In one embodiment, the invention is provides compounds capable ofaccumulating in human PBMC (peripheral blood mononuclear cells). PBMCrefer to blood cells having round lymphocytes and monocytes.Physiologically, PBMC are critical components of the mechanism againstinfection. PBMC may be isolated from heparinized whole blood of normalhealthy donors or buffy coats, by standard density gradientcentrifugation and harvested from the interface, washed (e.g.phosphate-buffered saline) and stored in freezing medium. PBMC may becultured in multi-well plates. At various times of culture, supernatantmay be either removed for assessment, or cells may be harvested andanalyzed (Smith R. et al (2003) Blood 102(7):2532-2540). The compoundsof this claim may further comprise a phosphonate or phosphonate prodrug.More typically, the phosphonate or phosphonate prodrug can have thestructure A³ as described herein.

Typically, compounds of the invention demonstrate improved intracellularhalf-life of the compounds or intracellular metabolites of the compoundsin human PBMC when compared to analogs of the compounds not having thephosphonate or phosphonate prodrug. Typically, the half-life is improvedby at least about 50%, more typically at least in the range 50-100%,still more typically at least about 100%, more typically yet greaterthan about 100%.

In one embodiment of the invention the intracellular half-life of ametabolite of the compound in human PBMCs is improved when compared toan analog of the compound not having the phosphonate or phosphonateprodrug. In such claims, the metabolite may be generatedintracellularly, e.g. generated within human PBMC. The metabolite may bea product of the cleavage of a phosphonate prodrug within human PBMCs.The phosphonate prodrug may be cleaved to form a metabolite having atleast one negative charge at physiological pH. The phosphonate prodrugmay be enzymatically cleaved within human PBMC to form a phosphonatehaving at least one active hydrogen atom of the form P—OH.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. All though only one delocalized resonance structure maybe depicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Monovalentsalts are preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or -organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occurring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

Methods of Treating Cancer

Another aspect of the invention relates to methods of treating cancer.Compositions of the invention may treat cancer, may act intermediatesfor such treatment or have other utilities as described below. Theanti-cancer compounds will bind to locations on the surface or in acavity of a cancer cell having a geometry unique to the anti-cancercompound. Compositions binding the anti-cancer compound may bind withvarying degrees of reversibility. Those compounds binding substantiallyirreversibly are ideal candidates for use in this method of theinvention. Once labeled, the substantially irreversibly bindingcompositions are useful as probes for the detection of cancer.Accordingly, the invention relates to methods of detecting cancer in asample suspected of containing cancer comprising the steps of: treatinga sample suspected of containing cancer with a composition comprising acompound of the invention bound to a label; and observing the effect ofthe sample on the activity of the label. Suitable labels are well knownin the diagnostics field and include stable free radicals, fluorophores,radioisotopes, enzymes, chemiluminescent groups and chromogens. Thecompounds herein are labeled in conventional fashion using functionalgroups such as hydroxyl or amino.

Within the context of the invention samples suspected of containingcancer include natural or man-made materials such as living organisms;tissue or cell cultures; biological samples such as biological materialsamples (blood, serum, urine, cerebrospinal fluid, tears, sputum,saliva, tissue samples, and the like); laboratory samples; food, water,or air samples; bioproduct samples such as extracts of cells,particularly recombinant cells synthesizing a desired glycoprotein; andthe like. Typically the sample will be suspected of containing cancer.Samples can be contained in any medium including water and organicsolvent/water mixtures. Samples include living organisms such as humans,and man made materials such as cell cultures.

The treating step of the invention comprises adding the composition ofthe invention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of cancer after application of the compositioncan be observed by any method including direct and indirect methods ofdetecting cancer activity. Quantitative, qualitative, andsemiquantitative methods of determining cancer activity are allcontemplated. Typically one of the screening methods described above areapplied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

Organisms that contain cancer include mammals such as humans. Thecompounds of this invention are useful in the treatment or prophylaxisof cancer in animals or in man.

However, in screening compounds capable of treating cancer it should bekept in mind that the results of enzyme assays may not correlate withcell culture assays. Thus, a cell based assay should be the primaryscreening tool.

Screens for Anti-Cancer Compounds

Compositions of the invention are screened for activity against cancerby any of the conventional techniques for evaluating enzyme activity.Within the context of the invention, typically compositions are firstscreened for activity against cancer in vitro and compositions showingactivity are then screened for activity in vivo. Useful in vitro screenshave been described in detail and will not be elaborated here. However,the examples describe suitable in vitro assays.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethyl cellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of cancerous infections as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active cancerousinfection, the method of delivery, and the pharmaceutical formulation,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day. Typically, from about 0.01 to about 10mg/kg body weight per day. More typically, from about 0.01 to about 5mg/kg body weight per day. More typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Active ingredients of the invention are also used in combination withother active ingredients. Such combinations are selected based on thecondition to be treated, cross-reactivities of ingredients andpharmaco-properties of the combination. For example, when treatingcancer, the compositions of the invention can be combined with otherchemotherapeutic agents. The second chemotherapeutic agent can be anysuitable compound that has biological activity against one or more formsof cancer.

It is also possible to combine any compound of the invention with one ormore other active ingredients in a unitary dosage form for simultaneousor sequential administration to an cancer patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations. Second and third active ingredients in thecombination may have chemotherapeutic activity and include any of theadditional chemotherapeutic agents described herein. Exemplary activeingredients to be administered in combination with compounds of theinvention are described below.

Suitable additional chemotherapeutic agents include, e.g., antracyclines(e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, andmitoxantrone); (b) other DNA intercalators (e.g., actinomycins C, D, B,etc.; podophyllotoxins, and epipodophyllatoxins (etoposide, teniposide,ctoposide)); (c) alkylating agents (e.g., mechlorethamine, melphalan,cyclophosphamide, chlorambucil, ifosfamide, carmustine, lomustine,busulfan, dacarbazine, cisplatin, carboplatin, oxaliplatin, iproplatin,and tetraplatin); (d) hormonal agents (e.g., antiestrogens/estrogenantagonists (tamoxifen and other SERMs); LHRH agonists and antagonists(leuprolide acetate, goserelin, abarelix); aromatase inhibitors; andantiandrogens; (e) chemoprevention agents (e.g., NSAIDs andcis-retinoids); and (f) cell-cycle chemopreventative agents.

Alternatively, the additional chemotherapeutic agent can include, e.g.,antineoplasts. Representative antineoplasts include, e.g., adjuncts(e.g., levamisole, gallium nitrate, granisetron, sargramostimstrontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, andondansetron); androgen inhibitors (e.g., flutamide and leuprolideacetate); antibiotic derivatives (e.g., doxorubicin, bleomycin sulfate,daunorubicin, dactinomycin, and idarubicin); antiestrogens (e.g.,tamoxifen citrate, analogs thereof, and nonsteroidal antiestrogens suchas toremifene, droloxifene and roloxifene); antimetabolites (e.g.,fludarabine phosphate, interferon alfa-2b recombinant, methotrexatesodium, plicamycin, mercaptopurine, and thioguanine); cytotoxic agents(e.g., doxorubicin, carmustine [BCNU], lomustine [CCNU], cytarabine USP,cyclophosphamide, estramucine phosphate sodium, altretamine,hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan,cyclophosphamide, mitoxantrone, carboplati, cisplati, cisplatin,interferon alfa-2a recombinant, paclitaxel, teniposide, andstreptozoci); hormones (e.g., medroxyprogesterone acetate, estradiol,megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate,testolactone, and goserelin acetate); immunomodulators (e.g.,aldesleukin); nitrogen mustard derivatives (e.g., melphalan,chlorambucil, mechlorethamine, and thiotepa) and steroids (betamethasonesodium phosphate and betamethasone acetate).

Suitable additional chemotherapeutic agents include, e.g., alkylatingagents, antimitotic agents, plant alkaloids, biologicals, topoisomeraseI inhibitors, topoisomerase II inhibitors, and synthetics.

Representative alkylating agents include, e.g., asaley, AZQ, BCNU,busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP,chlorambucil, chlorozotocin, cis-platinum, clomesone,cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide,dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, iphosphamide,melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard,PCNU, piperazine, piperazinedione, pipobroman, porfiromycin,spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin,thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864.

Representative antimitotic agents include, e.g., allocolchicine,Halichondrin B, colchicine, colchicine derivatives, dolastatin 10,maytansine, rhizoxin, paclitaxel derivatives, paclitaxel,thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristinesulfate.

Representative plant alkaloids include, e.g., actinomycin D, bleomycin,L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate,mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine andtaxotere.

Representative biologicals include, e.g., alpha interferon, BCG, G-CSF,GM-CSF, and interleukin-2.

Representative topoisomerase I inhibitors include, e.g., camptothecin,camptothecin derivatives, and morpholinodoxorubicin.

Representative topoisomerase II inhibitors include, e.g., mitoxantron,amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine,bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyldaunomycin, oxanthrazole, rubidazone, VM-26 and VP-16.

Representative synthetics include, e.g., hydroxyurea, procarbazine,o,p′-DDD, dacarbazine, CCNU, BCNU, cis-diamminedichloroplatimun,mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoicacid, gliadel and porfimer sodium.

Alternatively, the additional chemotherapeutic agent can includetubulin-binding drugs and drugs that affect tubulin dynamics andfunction. This includes a variety of drugs that are chemically unrelatedto vinca alkaloids and taxanes (e.g. CP-248 [a derivative of exisulind]and ILX-651). These drugs have distinctive effects on cells at G2M-phaseand may have functionally independent effects on cells in G1 and/or Sphase.

Alternatively, the additional chemotherapeutic agent can includeselective apoptotic anti-cancer drugs (SAANDs), which include sulindac,aptosyn, CP-461, CP-248 and related sulindac derived compounds thatinhibit one or more of the following isozymes of cyclic GMPphosphodiesterase (cGMP PDE): 1, 2, 5.

Alternatively, the additional chemotherapeutic agent can include drugsthat inhibit proteosomes (bortezomib or Velcade). Proteosomes degrademany ubiquitinated proteins that have been marked for activedestruction. Ubiquitinated proteins include many critical cell cycleregulatory molecules and molecules that regulate apoptosis at specificstages of the cell cycle. While proteosomes may degrade proteinsthroughout the cell cycle, the proteins that are degraded by proteosomesinclude some of the most critical cell cycle regulatory proteins. Theso-called “cell cycle active rationale” may be applied to the treatmentof diseases in various categories, including cancer,inflammatory/autoimmune diseases, and neurological diseases that involvedisorderly cell cycle and/or apoptosis.

Alternatively, the additional chemotherapeutic agent can include drugsthat inhibit heat shock protein 90 (HSP90), a ‘chaperonin’ thatparticipates in the degradation of ‘client’ proteins in the ubiquitinmediated proteosome pathway. Several drugs seem to exert theirantitumour effect by inhibiting the intrinsic ATPase activity of HSP90,resulting in degradation of HSP90 “client proteins” via the ubiquitinproteosome pathway. Examples include: geldanamycin, 17-allylaminogeldanamycin, 17-demethoxygeldanamycin and radicicol.

Suitable cell-cycle dependent biological agents or schedule-dependentbiological agents include drugs, proteins or other molecules that block,impede, or otherwise interfere with, cell cycle progression at theG1-phase, G1/S interface, S-phase, G2/M interface, or M-phase of thecell cycle. These drugs are cell cycle-dependent or schedule-dependent.

Specifically, suitable cell-cycle dependent biological agents orschedule-dependent biological agents include:

(1) Analogues of uridine nucleosides, analogues of thymidinenucleosides, and analogues of uridine and thymidine nucleosides. Thesecompounds act at the S-phase in tumor cells, and possibly neovascularendothelial cells. These compounds include, e.g., 5-fluorodeoxyuridine(floxuridine, FUDR); 5-fluorouracil (5-FU); prodrugs of 5-FU (e.g.capecitabine, 5′-deoxy-5-fluorouridine, ftorafur, flucytosine);bromodeoxyuridine; and iododexoyuridine.

(2) Modulators of fluoropyrimidines. These compounds act at the S-phasein tumor cells, and possibly neovascular endothelial cells. Thesecompounds include, e.g., leurovorin, methotrexate and other folates;levamisole; acivicin; phosphonacetyl-L-aspartic acid (PALA); brequinar;5-ethynyluracil; and uracil.

(3) Cytidine analogues and cytidine nucleoside analogues. Thesecompounds act at the S-phase in tumor cells, and possibly neovascularendothelial cells. These compounds include, e.g., cytarabine (Ara-C,cytosine arabinoside); gemcitabine (2′,2′-difluorodeoxycytidine); and5-azacytidine.

(4) Purine analogues and purine nucleoside analogues. These compoundsact at the S-phase in tumor cells, and possibly neovascular endothelialcells. These compounds include, e.g., 6-thioguanine; 6-mercaptopurine;azathioprine; adenosine arabinoside (Ara-A);2′,2′-difluorodeoxyguanosine; deoxycofommycin (pentostatin); cladribine(2-chlorodeoxyadenosine); and inhibitors of adenosine deaminase.

(5) Antifolates. These compounds act at the S-phase in tumor cells, andpossibly neovascular endothelial cells. These compounds include, e.g.,methotrexate; aminopterin; trimetrexate; edatrexate;N10-propargyl-5,8-dideazafolic acid (CB3717); ZD1694,5,8-dideazaisofolic acid (IAHQ); 5,10-dideazatetrahydrofolic acid(DDATHF); 5-deazafolic acid (efficient substrate for FPGS); PT523 (Nalpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine);10-ethyl-10-deazaminopterin (DDATHF, lomatrexol); piritrexim; 10-EDAM;ZD1694; GW1843; PDX (10-propargyl-10-deazaminopterin); multi-targetedfolate (i.e. LY231514, permetrexed); any folate-based inhibitor ofthymidylate synthase (TS); any folate-based inhibitor of dihydrofolatereductase (DHFR); any folate-based inhibitor of glycinamideribonucleotide transformylase (GARTF); any inhibitor offolylpolyglutamate synthetase (FPGS); and any folate-based inhibitor ofGAR formyl transferase (AICAR transformylase).

(6) Other antimetabolites. These compounds act at the S-phase in tumorcells, and possibly neovascular endothelial cells. These compoundsinclude, e.g., hydroxyurea and polyamines.

(7) S-phase specific radiotoxins (deoxythymidine analogues). Thesecompounds act at the S-phase in all cells undergoing DNA synthesis. Thecompounds are incorporated into chromosomal DNA during S-phase. Thesecompounds include, e.g., [125I]-iododeoxyuridine;[123I]-iododeoxyuridine; [124I]-iododeoxyuridine;[80mBr]-iododeoxyuridine; [131I]-iododeoxyuridine; and[211At]-astatine-deoxyuridine.

(8) Inhibitors of enzymes involved in deoxynucleoside/deoxynucleotidemetabolism. These compounds act at the S-phase in tumor cells, andpossibly neovascular endothelial cells. These compounds include, e.g.,inhibitors of thymidylate synthase (TS); inhibitors of dihydrofolatereductase (DHFR); inhibitors of glycinamide ribonucleotidetransformylase (GARTF); inhibitors of folylpolyglutamate synthetase(FPGS); inhibitors of GAR formyl transferase (AICAR transformylase);inhibitors of DNA polymerases (DNA Pol; e.g. aphidocolin); inhibitors ofribonucleotide reductase (RNR); inhibitors of thymidine kinase (TK); andinhibitors of topoisomerase I enzymes (e.g. camptothecins, irinotecan[CPT-11, camptosar], topotecan, NX-211 [lurtotecan], rubitecan, etc.).

(9) DNA chain-terminating nucleoside analogues. These compounds actspecifically on S-phase cells and are incorporated into chromosomal DNAduring S-phase; terminate growing DNA strand. These compounds include,e.g., acyclovir; abacavir; valacyclovir; zidovudine (AZT); didanosine(ddI, dideoxycytidine); zalcitabine (ddC); stavudine (D4T); lamivudine(3TC); Any 2′ 3′-dideoxy nucleoside analogue; and any 2′3′-dideoxynucleoside analogue that terminates DNA synthesis. These compoundsinclude, e.g., inhibitors of growth factor receptor tyrosine kinasesthat regulate progression through the G1-phase, G1/S interface, orS-phase of the cell cycle (e.g. EGF receptors, HER-2 neu/c-erbB2receptor, PDGF receptors, etc; [e.g. trastusumab, iressa, erbitux,tarceva]); inhibitors of non-receptor tyrosine kinases (e.g. c-srcfamily of tyrosine kinases; [e.g. Gleevec]); inhibitors ofserine-threonine kinases that regulate progression through the G1-phase,G1/S interface or S-phase of the cell cycle (e.g. G1 cyclin-dependentkinases, G1/S cyclin-dependent kinases, and S cyclin-dependent kinases[e.g. CDK2, CDK4, CDK5, CDK6]; mitogen-activated kinases; MAP kinasesignaling pathway); inhibitors of G1-phase, G1/S interface or S-phasecyclins [e.g. cyclins D1, D2, D3, E, and A]); inhibitors of G-proteinsand cGMP phosphodiesterases that positively regulate cell cycleprogression at the G1-phase, G1/S interface or S-phase of the cellcycle; drugs that inhibit the induction of immediate early responsetranscription factors (e.g. N-terminal c-jun kinase, c-myc); and drugsthat inhibit proteosomes that degrade ‘negative’ cell cycle regulatorymolecules (e.g. p53, p27/Kip1; [e.g. bortezomib]).

(10) Cytokines, growth factors, anti-angiogenic factors and otherproteins that inhibit cell cycle progression at the G1-phase or G1/Sinterface of the cell cycle. These compounds act at G1, G1/S or S-phaseof the cell cycle in tumor cells, and in some cases, neovascularendothelial cells. These compounds include, e.g., interferons;interleukins; somatostatin and somatostatin analogues (octreotide,sandostatin LAR); and many anti-angiogenic factors inhibit cellproliferation of endothelial cells at the G1 or G1/S phases of the cellcycle.

(11) Drugs and compounds that inhibit cell cycle progression at the G2/Minterface, or M-phase of the cell cycle. These compounds act at G2/Minterface or M-phase of the cell cycle in tumor cells, and in somecases, neovascular endothelial cells. These compounds include, e.g., (a)microtubule-targeting drugs—taxanes (e.g., taxol, taxotere, epothilones,and other taxanes and derivatives); (b) microtubule-targetingdrugs—vinca alkaloids (e.g., vinblastine, vincristine, vindesine;vinflunine, vinorelbine, vinzolidine, nocadazole, and colchicines); (c)microtubule-targeting drugs—others (e.g., estramustine, CP-248 andCP-461); (d) inhibitors of serine-threonine kinases that regulateprogression through the G2/M interface or M-phase of the cell cycle(e.g., inhibitors of G2/M cyclin-dependent kinases (e.g. CDC2);inhibitors of M-phase cyclins (e.g. cyclin B) and any drug that blocks,impedes, or otherwise interferes with, cell cycle progression at theG2/M interface, or M-phase of the cell cycle).

(12) Radiopharmaceuticals useful in radiation therapy and/or diagnosis.A suitable class of radioisotopes decay by a nuclear disintegrationprocess known as the “Auger Process” or “Auger Cascade”. Auger emittingisotopes generate short acting electrons that efficiently cleave duplexDNA. Suitable Auger-emitting radionuclides include, e.g., 125-Iodine,123-Iodine and 80m-Bromine. Suitable corresponding halogenatedpryimidine and purine nucleosides include, e.g.,5-125Iodo-2′-deoxyuridine, 5-123Iodo-2′-deoxyuridine, 5-80mBromo-2′-deoxyuridine and 8-80 mBromo-2′-guanidine.

Growth Factors

Many growth factors and cytokines have the capacity to stimulatemalignant cells to traverse specific points in the cell cycle. Forexample, G-CSF or GM-CSF can stimulate leukemic blasts in acute mycloidleukemia to traverse the G1/S interface. This increases the cells'susceptibility to cell-cycle specific drugs, such as cytarabine. Similarstrategies have been tested using EGF and cytotoxic drugs for solidtumors. In order to respond the growth factor, cells must be at aspecific stage of the cell cycle, e.g., at the G1/S interface. Thecontinuous presence of a growth factor could be beneficial, because atany given time, only a subset of the blasts are at G1/S. Thus, thegrowth factors act in a cell cycle specific fashion. Similar logic canbe applied to the use of hematopoietic growth factors used to treatneutropenia, anemia and thrombocytopenia.

As such, peptide/protein growth factors can be employed in the presentinvention to promote survival of normal non-malignant cell lineages. Onebenefit in using such substances is the ability to protect proliferatingcells in bone marrow, skin, oral and gastrointestinal mucosa, and hairfollicles.

Examples of substances within this category include, e.g., hematopoieticgrowth factors: G-CSF, GM-CSF, erythropoietin, thrombopoietin andbiologically active derivatives of these peptides; keratinocyte growthfactor (KGF) for mucositis; B-lymphocyte stimulating pepdie (BLys);platelet derived growth factor (PDGF), epithelial growth factor (EGF),TGF-alpha and related growth factors; interleukins (e.g. IL-2, IL-6);other cytokines, growth factors and peptides that stimulateproliferation of non-malignant cells that need to be protected.

Therapeutic Growth Factors/Cytokines

Some therapeutic growth factors/cytokines can inhibit cell proliferationof cancer cells and/or neovascular cells at specific stages of the cellcycle. For example, interferons, somatostatin, octreotide and analoguesthereof, thrombospondin and troponin-I inhibit neovascular endothelialcell proliferation by reducing the rate at which the cells enterS-phase. As such, any one or more of these substances can be employed inthe present invention.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noanti-cancer activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The phosphonate prodrugs of theinvention typically will be stable in the digestive system but aresubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

In one embodiment of the invention, the compound is in an isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is substantially free from biological materials (e.g.blood, tissue, cells, etc.). In one specific embodiment of theinvention, the term means that the compound or conjugate of theinvention is at least about 50 wt. % free from biological materials; inanother specific embodiment, the term means that the compound orconjugate of the invention is at least about 75 wt. % free frombiological materials; in another specific embodiment, the term meansthat the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 98 wt. % free from biological materials; and in anotherembodiment, the term means that the compound or conjugate of theinvention is at least about 99 wt. % free from biological materials. Inanother specific embodiment, the invention provides a compound orconjugate of the invention that has been synthetically prepared (e.g.,ex vivo).

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis, Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

A number of exemplary methods for the preparation of the compositions ofthe invention are provided below. These methods are intended toillustrate the nature of such preparations are not intended to limit thescope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

SCHEMES AND EXAMPLES

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched xanthene. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

EXAMPLES GENERAL SECTION

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples hereinbelow.These methods are intended to illustrate the nature of such preparationsare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. For example, theinterconversion of various phosphonate compounds of the invention isillustrated below.

Interconversions of the Phosphonates R-Link-P(O)(OR¹)₂,R-Link-P(O)(OR¹)(OH) and R-Link-P(O)(OH)₂.

The following Schemes 32-38 described the preparation of phosphonateesters of the general structure R-link-P(O)(OR¹)₂, in which the groupsR¹ may be the same or different. The R¹ groups attached to a phosphonateester, or to precursors thereto, may be changed using establishedchemical transformations. The interconversion reactions of phosphonatesare illustrated in Scheme S32. The group R in Scheme 32 represents thesubstructure, i.e. the drug “scaffold, to which the substituentlink-P(O)(OR¹)₂ is attached, either in the compounds of the invention,or in precursors thereto. At the point in the synthetic route ofconducting a phosphonate interconversion, certain functional groups in Rmay be protected. The methods employed for a given phosphonatetransformation depend on the nature of the substituent R¹, and of thesubstrate to which the phosphonate group is attached. The preparationand hydrolysis of phosphonate esters is described in Organic PhosphorusCompounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.

In general, synthesis of phosphonate esters is achieved by coupling anucleophile amine or alcohol with the corresponding activatedphosphonate electrophilic precursor. For example, chlorophosphonateaddition on to 5′-hydroxy of nucleoside is a well known method forpreparation of nucleoside phosphate monoesters. The activated precursorcan be prepared by several well known methods. Chlorophosphonates usefulfor synthesis of the prodrugs are prepared from thesubstituted-1,3-propanediol (Wissner, et al, (1992) J. Med Chem.35:1650). Chlorophosphonates are made by oxidation of the correspondingchlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) whichare obtained by reaction of the substituted diol with phosphorustrichloride. Alternatively, the chlorophosphonate agent is made bytreating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonatespecies may also be generated in situ from corresponding cyclicphosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774),which in turn can be either made from chlorophospholane orphosphoramidate intermediate. Phosphoroflouridate intermediate preparedeither from pyrophosphate or phosphoric acid may also act as precursorin preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedronlett., 29:5763-66).

Phosphonate prodrugs of the present invention may also be prepared fromthe free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;Campbell, (1992) J. Org. Chem. 57:6331), and other acid couplingreagents including, but not limited to, carbodiimides (Alexander, et al,(1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992)Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett.,29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts(Campagne et al (1993) Tetrahedron Lett. 34:6743).

Aryl halides undergo Ni⁺² catalyzed reaction with phosphite derivativesto give aryl phosphonate containing compounds (Balthazar, et al (1980)J. Org. Chem. 45:5425). Phosphonates may also be prepared from thechlorophosphonate in the presence of a palladium catalyst using aromatictriflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al(1987) Synthesis 726). In another method, aryl phosphonate esters areprepared from aryl phosphates under anionic rearrangement conditions(Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991)Synthesis, 691). N-Alkoxy aryl salts with alkali metal derivatives ofcyclic alkyl phosphonate provide general synthesis forheteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).These above mentioned methods can also be extended to compounds wherethe W⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs ofphosphonates are also synthesized from phosphonic diacids andsubstituted propane-1,3-diols using a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,pyridine). Other carbodiimide based coupling agents like1,3-disopropylcarbodiimide or water soluble reagent,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) canalso be utilized for the synthesis of cyclic phosphonate prodrugs.

The conversion of a phosphonate diester S32.1 into the correspondingphosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by anumber of methods. For example, the ester S32.1 in which R¹ is anaralkyl group such as benzyl, is converted into the monoester compoundS32.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 110° C. The conversion ofthe diester S32.1 in which R¹ is an aryl group such as phenyl, or analkenyl group such as allyl, into the monoester S32.2 is effected bytreatment of the ester S32.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters S32.1 in which one of the groupsR¹ is aralkyl, such as benzyl, and the other is alkyl, is converted intothe monoesters S32.2 in which R¹ is alkyl by hydrogenation, for exampleusing a palladium on carbon catalyst. Phosphonate diesters in which bothof the groups R¹ are alkenyl, such as allyl, is converted into themonoester S32.2 in which R¹ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem. (1973)38:3224, for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester S32.1 or a phosphonate monoesterS32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions2 and 3) can be effected by reaction of the diester or the monoesterwith trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,(1979) 739. The reaction is conducted in an inert solvent such as, forexample, dichloromethane, optionally in the presence of a silylatingagent such as bis(trimethylsilyl)trifluoroacetamide, at ambienttemperature. A phosphonate monoester S32.2 in which R¹ is aralkyl suchas benzyl, is converted into the corresponding phosphonic acid S32.3 byhydrogenation over a palladium catalyst, or by treatment with hydrogenchloride in an ethereal solvent such as dioxane. A phosphonate monoesterS32.2 in which R¹ is alkenyl such as, for example, allyl, is convertedinto the phosphonic acid S32.3 by reaction with Wilkinson's catalyst inan aqueous organic solvent, for example in 15% aqueous acetonitrile, orin aqueous ethanol, for example using the procedure described in Helv.Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis ofphosphonate esters S32.1 in which R¹ is benzyl is described in J. Org.Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonateesters S32.1 in which R¹ is phenyl is described in J. Am. Chem. Soc.(1956) 78:2336.

The conversion of a phosphonate monoester S32.2 into a phosphonatediester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R¹group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl iseffected by a number of reactions in which the substrate S32.2 isreacted with a hydroxy compound R¹OH, in the presence of a couplingagent. Typically, the second phosphonate ester group is different thanthe first introduced phosphonate ester group, i.e. R¹ is followed by theintroduction of R² where each of R¹ and R² is alkyl, aralkyl, haloalkylsuch as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2is converted to S32.1a. Suitable coupling agents are those employed forthe preparation of carboxylate esters, and include a carbodiimide suchas dicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester S32.2 to thediester S32.1 is effected by the use of the Mitsunobu reaction, asdescribed above (Scheme 7). The substrate is reacted with the hydroxycompound R¹OH, in the presence of diethyl azodicarboxylate and atriarylphosphine such as triphenyl phosphine. Alternatively, thephosphonate monoester S32.2 is transformed into the phosphonate diesterS32.1, in which the introduced R¹ group is alkenyl or aralkyl, byreaction of the monoester with the halide R¹Br, in which R¹ is asalkenyl or aralkyl. The alkylation reaction is conducted in a polarorganic solvent such as dimethylformamide or acetonitrile, in thepresence of a base such as cesium carbonate. Alternatively, thephosphonate monoester is transformed into the phosphonate diester in atwo step procedure. In the first step, the phosphonate monoester S32.2is transformed into the chloro analog RP(O)(OR¹)Cl by reaction withthionyl chloride or oxalyl chloride and the like, as described inOrganic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley,1976, p. 17, and the thus-obtained product RP(O)(OR¹)Cl is then reactedwith the hydroxy compound R¹OH, in the presence of a base such astriethylamine, to afford the phosphonate diester S32.1.

A phosphonic acid R-link-P(O)(OH)₂ is transformed into a phosphonatemonoester RP(O)(OR¹)(OH) (Scheme 32, Reaction 5) by means of the methodsdescribed above of for the preparation of the phosphonate diesterR-link-P(O)(OR¹)₂ S32.1, except that only one molar proportion of thecomponent R¹OH or R¹Br is employed. Dialkyl phosphonates may be preparedaccording to the methods of: Quast et al (1974) Synthesis 490; Stowellet al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.

A phosphonic acid R-link-P(O)(OH)₂ S32.3 is transformed into aphosphonate diester R-link-P(O)(OR¹)₂ S32.1 (Scheme 32, Reaction 6) by acoupling reaction with the hydroxy compound R¹OH, in the presence of acoupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.The reaction is conducted in a basic solvent such as pyridine.Alternatively, phosphonic acids S323 are transformed into phosphonicesters S32.1 in which R¹ is aryl, by means of a coupling reactionemploying, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is alkenyl, by means of an alkylation reaction.The phosphonic acid is reacted with the alkenyl bromide R¹Br in a polarorganic solvent such as acetonitrile solution at reflux temperature, thepresence of a base such as cesium carbonate, to afford the phosphonicester S32.1.

Preparation of Phosphonate Carbamates.

Phosphonate esters may contain a carbamate linkage. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formedby reaction of a hydroxy group according to the methods known in theart, including the teachings of Ellis, US 2002/0103378 A1 and Hajima,U.S. Pat. No. 6,018,049.

Scheme 33 illustrates various methods by which the carbamate linkage issynthesized. As shown in Scheme 33, in the general reaction generatingcarbamates, an alcohol S33.1, is converted into the activated derivativeS33.2 in which Lv is a leaving group such as halo, imidazolyl,benztriazolyl and the like, as described herein. The activatedderivative S33.2 is then reacted with an amine S33.3, to afford thecarbamate product S33.4. Examples 1-7 in Scheme 33 depict methods bywhich the general reaction is effected. Examples 8-10 illustratealternative methods for the preparation of carbamates.

Scheme 33, Example 1 illustrates the preparation of carbamates employinga chloroformyl derivative of the alcohol S33.5. In this procedure, thealcohol S33.5 is reacted with phosgene, in an inert solvent such astoluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167,1965, or with an equivalent reagent such as trichloromethoxychloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, toafford the chloroformate S33.6. The latter compound is then reacted withthe amine component S33.3, in the presence of an organic or inorganicbase, to afford the carbamate S33.7. For example, the chloroformylcompound S33.6 is reacted with the amine S33.3 in a water-misciblesolvent such as tetrahydrofuran, in the presence of aqueous sodiumhydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yieldthe carbamate S33.7. Alternatively, the reaction is performed indichloromethane in the presence of an organic base such asdiisopropylethylamine or dimethylaminopyridine.

Scheme 33, Example 2 depicts the reaction of the chloroformate compoundS33.6 with imidazole to produce the imidazolide S33.8. The imidazolideproduct is then reacted with the amine S33.3 to yield the carbamateS33.7. The preparation of the imidazolide is performed in an aproticsolvent such as dichloromethane at 0°, and the preparation of thecarbamate is conducted in a similar solvent at ambient temperature,optionally in the presence of a base such as dimethylaminopyridine, asdescribed in J. Med. Chem., 1989, 32, 357.

Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6with an activated hydroxyl compound R″OH, to yield the mixed carbonateester S33.10. The reaction is conducted in an inert organic solvent suchas ether or dichloromethane, in the presence of a base such asdicyclohexylamine or triethylamine. The hydroxyl component R″OH isselected from the group of compounds S33.19-S33.24 shown in Scheme 33,and similar compounds. For example, if the component R″OH ishydroxybenztriazole S33.19, N-hydroxysuccinimide S33.20, orpentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by thereaction of the chloroformate with the hydroxyl compound in an etherealsolvent in the presence of dicyclohexylamine, as described in Can. J.Chem., 1982, 60, 976. A similar reaction in which the component R″OH ispentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in anethereal solvent in the presence of triethylamine, as described in Syn.,1986, 303, and Chem. Ber. 118, 468, 1985.

Scheme 33 Example 4 illustrates the preparation of carbamates in whichan alkyloxycarbonylimidazole S33.8 is employed. In this procedure, analcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare the intermediate S33.8. The reaction isconducted in an aprotic organic solvent such as dichloromethane ortetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is performed in an aprotic organic solvent such asdichloromethane, as described in Tet. Lett., 42, 2001, 5227, to affordthe carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamates by meansof an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure,an alcohol ROH is reacted at ambient temperature with an equimolaramount of benztriazole carbonyl chloride S33.12, to afford thealkoxycarbonyl product S33.13. The reaction is performed in an organicsolvent such as benzene or toluene, in the presence of a tertiaryorganic amine such as triethylamine, as described in Synthesis., 1977,704. The product is then reacted with the amine R′NH₂ to afford thecarbamate S33.7. The reaction is conducted in toluene or ethanol, atfrom ambient temperature to about 80° C. as described in Synthesis.,1977, 704.

Scheme 33, Example 6 illustrates the preparation of carbamates in whicha carbonate (R″O)₂CO, S33.14, is reacted with an alcohol S33.5 to affordthe intermediate alkyloxycarbonyl intermediate S33.15. The latterreagent is then reacted with the amine R′NH₂ to afford the carbamateS33.7. The procedure in which the reagent S33.15 is derived fromhydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; theprocedure in which the reagent S33.15 is derived fromN-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; theprocedure in which the reagent S33.15 is derived from 2-hydroxypyridineS33.23 is described in Tet. Lett., 1991, 4251; the procedure in whichthe reagent S33.15 is derived from 4-nitrophenol S33.24 is described inSynthesis. 1993, 103. The reaction between equimolar amounts of thealcohol ROH and the carbonate S33.14 is conducted in an inert organicsolvent at ambient temperature.

Scheme 33, Example 7 illustrates the preparation of carbamates fromalkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformateS33.6 is reacted with an azide, for example sodium azide, to afford thealkoxycarbonyl azide S33.16. The latter compound is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is conducted at ambient temperature in a polar aprotic solventsuch as dimethylsulfoxide, for example as described in Synthesis., 1982,404.

Scheme 33, Example 8 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and the chloroformyl derivativeof an amine S33.17. In this procedure, which is described in SyntheticOrganic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, thereactants are combined at ambient temperature in an aprotic solvent suchas acetonitrile, in the presence of a base such as triethylamine, toafford the carbamate S33.7.

Scheme 33, Example 9 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an isocyanate S33.18. In thisprocedure, which is described in Synthetic Organic Chemistry, R. B.Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined atambient temperature in an aprotic solvent such as ether ordichloromethane and the like, to afford the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an amine R′NH₂. In thisprocedure, which is described in Chem. Lett. 1972, 373, the reactantsare combined at ambient temperature in an aprotic organic solvent suchas tetrahydrofuran, in the presence of a tertiary base such astriethylamine, and selenium. Carbon monoxide is passed through thesolution and the reaction proceeds to afford the carbamate S33.7.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride or withtriisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996)7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activatedsulfonyloxy derivatives are then reacted with amines or hydroxycompounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987)52:2792. The use of ethyl dimethylaminopropyl carbodiimide foractivation and coupling of phosphonic acids is described in Tet. Lett.,(2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J.Org. Chem. (1984) 49:1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett. (1998) 8:1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., (1996) 37:3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsunobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., 1, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 34-37 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphonbisamidates(Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters(Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustratessynthesis of gem-dialkyl amino phosphonate reagents.

Scheme 34 illustrates various methods for the conversion of phosphonatediesters S34.1 into phosphonbisamidates S34.5. The diester S34.1,prepared as described previously, is hydrolyzed, either to the monoesterS34.2 or to the phosphonic acid S34.6. The methods employed for thesetransformations are described above. The monoester S34.2 is convertedinto the monoamidate S34.3 by reaction with an aminoester S34.9, inwhich the group R² is H or alkyl; the group R^(4b) is a divalentalkylene moiety such as, for example, CHCH₃, CHCH₂CH₃, CH(CH(CH₃)₂),CH(CH₂Ph), and the like, or a side chain group present in natural ormodified aminoacids; and the group R^(5b) is C₁-C₁₂ alkyl, such asmethyl, ethyl, propyl, isopropyl, or isobutyl; C₆-C₂₀ aryl, such asphenyl or substituted phenyl; or C₆-C₂₀ arylalkyl, such as benzyl orbenzyhydryl. The reactants are combined in the presence of a couplingagent such as a carbodiimide, for example dicyclohexyl carbodiimide, asdescribed in J. Am. Chem. Soc., (1957) 79:3575, optionally in thepresence of an activating agent such as hydroxybenztriazole, to yieldthe amidate product S34.3. The amidate-forming reaction is also effectedin the presence of coupling agents such as BOP, as described in J. Org.Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents usedfor the preparation of amides and esters. Alternatively, the reactantsS34.2 and S34.9 are transformed into the monoamidate S34.3 by means of aMitsunobu reaction. The preparation of amidates by means of theMitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.Equimolar amounts of the reactants are combined in an inert solvent suchas tetrahydrofuran in the presence of a triaryl phosphine and a dialkylazodicarboxylate. The thus-obtained monoamidate ester S34.3 is thentransformed into amidate phosphonic acid S34.4. The conditions used forthe hydrolysis reaction depend on the nature of the R¹ group, asdescribed previously. The phosphonic acid amidate S34.4 is then reactedwith an aminoester S34.9, as described above, to yield the bisamidateproduct S34.5, in which the amino substituents are the same ordifferent. Alternatively, the phosphonic acid S34.6 may be treated withtwo different amino ester reagents simulataneously, i.e. S34.9 where R²,R^(4b) or R^(5b) are different. The resulting mixture of bisamidateproducts S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In thisprocedure, a dibenzyl phosphonate S34.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate S34.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate S34.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate productS34.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product S34.18 which maybe unstable according to J. Med. Chem. (1997) 40(23):3842. This compoundS34.18 is then reacted in a Mitsunobu reaction with ethyl leucinateS34.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20.

Using the above procedures, but employing in place of ethyl leucinateS34.19 or ethyl alaninate S34.16, different aminoesters S34.9, thecorresponding products S34.5 are obtained.

Alternatively, the phosphonic acid S34.6 is converted into thebisamidate S34.5 by use of the coupling reactions described above. Thereaction is performed in one step, in which case the nitrogen-relatedsubstituents present in the product S34.5 are the same, or in two steps,in which case the nitrogen-related substituents can be different.

An example of the method is shown in Scheme 34, Example 2. In thisprocedure, a phosphonic acid S34.6 is reacted in pyridine solution withexcess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product S34.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters S34.9, the corresponding productsS34.5 are obtained.

As a further alternative, the phosphonic acid S34.6 is converted intothe mono or bis-activated derivative S34.7, in which Lv is a leavinggroup such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.The conversion of phosphonic acids into chlorides S34.7 (Lv=Cl) iseffected by reaction with thionyl chloride or oxalyl chloride and thelike, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester S34.9, in the presence of a base, to give the bisamidateS34.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product S34.5 are the same, or in two steps,via the intermediate S34.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 34, Examples 3 and 5. Inthe procedure illustrated in Scheme 34, Example 3, a phosphonic acidS34.6 is reacted with ten molar equivalents of thionyl chloride, asdescribed in Zh. Obschei Khim., 1958, 28, 1063, to give the dichlorocompound S34.23. The product is then reacted at reflux temperature in apolar aprotic solvent such as acetonitrile, and in the presence of abase such as triethylamine, with butyl serinate S34.24 to afford thebisamidate product S34.25.

Using the above procedures, but employing, in place of butyl serinateS34.24, different aminoesters S34.9, the corresponding products S34.5are obtained.

In the procedure illustrated in Scheme 34, Example 5, the phosphonicacid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991,312, with carbonyl diimidazole to give the imidazolide S34.32. Theproduct is then reacted in acetonitrile solution at ambient temperature,with one molar equivalent of ethyl alaninate S34.33 to yield themonodisplacement product S34.34. The latter compound is then reactedwith carbonyl diimidazole to produce the activated intermediate S34.35,and the product is then reacted, under the same conditions, with ethylN-methylalaninate S34.33a to give the bisamidate product S34.36.

Using the above procedures, but employing, in place of ethyl alaninateS34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9,the corresponding products S34.5 are obtained.

The intermediate monoamidate S34.3 is also prepared from the monoesterS34.2 by first converting the monoester into the activated derivativeS34.8 in which Lv is a leaving group such as halo, imidazolyl etc, usingthe procedures described above. The product S34.8 is then reacted withan aminoester S34.9 in the presence of a base such as pyridine, to givean intermediate monoamidate product S34.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester S34.9, as described above, into the bisamidate S34.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative S34.26, is shown in Scheme 34,Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 toyield the monoamidate product S34.28. The latter compound ishydrogenated in ethylacetate over a 5% palladium on carbon catalyst toproduce the monoacid product S34.29. The product is subjected to aMitsunobu coupling procedure, with equimolar amounts of butyl alaninateS34.30, triphenyl phosphine, diethylazodicarboxylate and triethylaminein tetrahydrofuran, to give the bisamidate product S34.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30, differentaminoesters S34.9, the corresponding products S34.5 are obtained.

The activated phosphonic acid derivative S34.7 is also converted intothe bisamidate S34.5 via the diamino compound S34.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs S34.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The bisamino compound S34.10 is then reacted atelevated temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl,Br, I), in a polar organic solvent such as dimethylformamide, in thepresence of a base such as 4,4-dimethylaminopyridine (DMAP) or potassiumcarbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may betreated with two different amino ester reagents simulataneously, i.e.S34.12 where R^(4b) or R^(5b) are different. The resulting mixture ofbisamidate products S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 6. In thismethod, a dichlorophosphonate S34.23 is reacted with ammonia to affordthe diamide S34.37. The reaction is performed in aqueous, aqueousalcoholic or alcoholic solution, at reflux temperature. The resultingdiamino compound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product S34.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 thecorresponding products S34.5 are obtained.

The procedures shown in Scheme 34 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups. Scheme 34, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, asdescribed in Example 5, to yield the monoamidate S34.41. The product isreacted with carbonyl diimidazole to give the imidazolide S34.42, andthis material is reacted with a further molar equivalent of propyltyrosinate to produce the bisamidate product S34.43.

Using the above procedures, but employing, in place of propyl tyrosinateS34.40, different aminoesters S34.9, the corresponding products S34.5are obtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 35 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester S34.1 is converted, asdescribed in Scheme 34, into the activated derivative S34.8. Thiscompound is then reacted, as described above, with an aminoester S34.9,in the presence of a base, to afford the monoamidate product S35.1.

The procedure is illustrated in Scheme 35, Example 1. In this method, amonophenyl phosphonate S35.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product S35.8. The product is then reacted, as described inScheme 34, with ethyl alaninate S3, to yield the amidate S35.10.

Using the above procedures, but employing, in place of ethyl alaninateS35.9, different aminoesters S34.9, the corresponding products S35.1 areobtained.

Alternatively, the phosphonate monoester S34.1 is coupled, as describedin Scheme 34, with an aminoester S34.9 to produce the amidate S34.5. Ifnecessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid S35.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate productS35.3, by reaction with the hydroxy compound R³OH, in which the group R³is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobureaction etc) described in Scheme 34 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 35, Examples 1, 2 and 3. Inthe sequence shown in Example 2, a monobenzyl phosphonate S35.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate S35.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidateS35.13. The product is then reacted in dichloromethane solution atambient temperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester S35.15.

In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine S35.16, to produce the amidate esterproduct S35.17.

Using the above procedures, but employing, in place of the ethylalaninate product S35.12 different monoacids S35.2, and in place oftrifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16,different hydroxy compounds R³OH, the corresponding products S35.3 areobtained.

Alternatively, the activated phosphonate ester S34.8 is reacted withammonia to yield the amidate S35.4. The product is then reacted, asdescribed in Scheme 34, with a haloester S35.5, in the presence of abase, to produce the amidate product S35.6. If appropriate, the natureof the R¹ group is changed, using the procedures described above, togive the product S35.3. The method is illustrated in Scheme 35, Example4. In this sequence, the monophenyl phosphoryl chloride S35.18 isreacted, as described in Scheme 34, with ammonia, to yield the aminoproduct S35.19. This material is then reacted in N-methylpyrrolidinonesolution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 andpotassium carbonate, to afford the amidate product S35.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, thecorresponding products S35.6 are obtained.

The monoamidate products S35.3 are also prepared from the doublyactivated phosphonate derivatives S34.7. In this procedure, examples ofwhich are described in Synlett., 1998, 1, 73, the intermediate S34.7 isreacted with a limited amount of the aminoester S34.9 to give themono-displacement product S34.11. The latter compound is then reactedwith the hydroxy compound R³OH in a polar organic solvent such asdimethylformamide, in the presence of a base such asdiisopropylethylamine, to yield the monoamidate ester S35.3.

The method is illustrated in Scheme 35, Example 5. In this method, thephosphoryl dichloride S35.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate S35.23 anddimethylaminopyridine, to generate the monoamidate S35.24. The productis then reacted with phenol S35.25 in dimethylformamide containingpotassium carbonate, to yield the ester amidate product S35.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate S35.23 or phenol S35.25, the aminoesters 34.9 and/or thehydroxy compounds R³OH, the corresponding products S35.3 are obtained.

Scheme 36 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester S34.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester S36.1, in which the groups R^(4b) and R^(5b) are asdescribed in Scheme 34. For example, equimolar amounts of the reactantsare coupled in the presence of a carbodiimide such as dicyclohexylcarbodiimide, as described in Aust. J. Chem., 1963, 609, optionally inthe presence of dimethylaminopyridine, as described in Tet., 1999, 55,12997. The reaction is conducted in an inert solvent at ambienttemperature.

The procedure is illustrated in Scheme 36, Example 1. In this method, amonophenyl phosphonate S36.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate S36.10 to yield the phosphonate mixeddiester S36.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1, thecorresponding products S33.2 are obtained.

The conversion of a phosphonate monoester S34.1 into a mixed diesterS36.2 is also accomplished by means of a Mitsunobu coupling reactionwith the hydroxyester S36.1, as described in Org. Lett., 2001, 643. Inthis method, the reactants S34.1 and S36.1 are combined in a polarsolvent such as tetrahydrofuran, in the presence of a triarylphosphineand a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R¹substituent is varied by cleavage, using the methods describedpreviously, to afford the monoacid product S36.3. The product is thencoupled, for example using methods described above, with the hydroxycompound R³OH, to give the diester product S36.4.

The procedure is illustrated in Scheme 36, Example 2. In this method, amonoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate S36.13 to give the mixed diester S36.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product S36.15. The latter compound isthen coupled, in pyridine solution at ambient temperature, in thepresence of dicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine S36.16 to yield the mixed diester S36.17.

Using the above procedures, but employing, in place of the ethyl lactateS36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or adifferent hydroxy compound R³OH, the corresponding products S36.4 areobtained.

The mixed diesters S36.2 are also obtained from the monoesters S34.1 viathe intermediacy of the activated monoesters S36.5. In this procedure,the monoester S34.1 is converted into the activated compound S36.5 byreaction with, for example, phosphorus pentachloride, as described in J.Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyesterS36.1, as described above, to yield the mixed diester S36.2.

The procedure is illustrated in Scheme 36, Example 3. In this sequence,a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at70° C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride S36.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containingtriethylamine, to give the mixed diester S36.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, thecorresponding products S36.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³O group into intermediates S36.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate S36.3 is converted into the activated derivativeS36.6 in which Lv is a leaving group such as chloro, imidazole, and thelike, as previously described. The activated intermediate is thenreacted with the hydroxy compound R³OH, in the presence of a base, toyield the mixed diester product S36.4.

The method is illustrated in Scheme 36, Example 4. In this sequence, thephosphonate monoacid S36.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct S36.23. This compound is reacted with 3-(morpholinomethyl)phenolS36.24 in dichloromethane containing triethylamine, to yield the mixeddiester product S36.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol S36.24, different alcohols R³OH, thecorresponding products S36.4 are obtained.

The phosphonate esters S36.4 are also obtained by means of alkylationreactions performed on the monoesters S34.1. The reaction between themonoacid S34.1 and the haloester S36.7 is performed in a polar solventin the presence of a base such as diisopropylethylamine, as described inAnal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 36, Example 5. In this procedure,the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionateS36.27 and diisopropylethylamine in dimethylformamide at 80° C. toafford the mixed diester product S36.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, thecorresponding products S36.4 are obtained.

Scheme 37 illustrates methods for the preparation of phosphonatediesters in which both the ester substituents incorporate carboalkoxygroups.

The compounds are prepared directly or indirectly from the phosphonicacids S34.6. In one alternative, the phosphonic acid is coupled with thehydroxyester S37.2, using the conditions described previously in Schemes34-36, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsunobu reaction, toafford the diester product S37.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 37, Example 1. In this procedure,the phosphonic acid S34.6 is reacted with three molar equivalents ofbutyl lactate S37.5 in the presence of Aldrithiol-2 and triphenylphosphine in pyridine at ca. 70° C., to afford the diester S37.6.

Using the above procedure, but employing, in place of butyl lactateS37.5, different hydroxyesters S37.2, the corresponding products S37.3are obtained.

Alternatively, the diesters S37.3 are obtained by alkylation of thephosphonic acid S34.6 with a haloester S37.1. The alkylation reaction isperformed as described in Scheme 36 for the preparation of the estersS36.4.

This method is illustrated in Scheme 37, Example 2. In this procedure,the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-methylpropionate S37.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester S37.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate S37.7, different haloesters S37.1, thecorresponding products S37.3 are obtained.

The diesters S37.3 are also obtained by displacement reactions ofactivated derivatives S34.7 of the phosphonic acid with thehydroxyesters S37.2. The displacement reaction is performed in a polarsolvent in the presence of a suitable base, as described in Scheme 36.The displacement reaction is performed in the presence of an excess ofthe hydroxyester, to afford the diester product S37.3 in which the estersubstituents are identical, or sequentially with limited amounts ofdifferent hydroxyesters, to prepare diesters S37.3 in which the estersubstituents are different.

The methods are illustrated in Scheme 37, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride S35.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct S37.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate S37.9, different hydroxyestersS37.2, the corresponding products S37.3 are obtained.

Scheme 37, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride S35.22 and ethyl2-methyl-3-hydroxypropionate S37.11, to yield the monoester productS37.12. The reaction is conducted in acetonitrile at 70° in the presenceof diisopropylethylamine. The product S37.12 is then reacted, under thesame conditions, with one molar equivalent of ethyl lactate S37.13, togive the diester product S37.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13, sequentialreactions with different hydroxyesters S37.2, the corresponding productsS37.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12.Acidic methanolysis of S38.12 provide amine S38.13. Protection of aminewith Cbz group and removal of methyl groups yield phosphonic acidS38.14, which can be converted to desired S38.15 (Scheme 38a) usingmethods reported earlier on. An alternative synthesis of compound S38.14is also shown in Scheme 38b. Commercially available2-amino-2-methyl-1-propanol is converted to aziridines S38.16 accordingto literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8,893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett.1980, 21, 1623). Reprotection) of S38.17 affords S38.14.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 Preparation of Exemplary Compounds of the PresentInvention

Schemes 1.1-1.3 illustrate the synthesis of target molecules of types1-12 and 1-56, in which the link is a heteroatom and carbon chain. Thepreparation of 1-1 is described in U.S. Pat. No. 5,770,596. Diether 1-1is converted into mono ether 1-2 as described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, ThirdEdition (1999) p. 246, or by the method described in U.S. Pat. No.5,770,596. Preferably diether 1-1 in methanesulfonic acid is treatedwith L-methionine at reflux to give the phenol 1-2. Phenol 1-2 is thenprotected as the acetyl compound 1-3 and then converted to the chloride1-4. These procedures are described in U.S. Pat. No. 5,770,596. Theacetoxy compound is then treated with the aniline 1-5 to give the amine1.6 followed by deprotection of the acetyl group to give 1-7 asdescribed in U.S. Pat. No. 5,770,596. Treatment of 1-7 withepibromohydrin 1-8 (Aldrich) in DMF with potassium carbonate presentthen affords the epoxide 1-9. Treatment of epoxide 1-9 with morpholinein a non-protic solvent at reflux in the presence of a base such astriethylamine affords the alcohol 1-10. The alcohol 1-10 is treated withone equivalent of the phosphonate alkylating agent, in which Lv is agroup such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl etc, inthe presence of base e.g. potassium or cesium carbonate in DMF, to givethe ether 1-12, in which the link is an oxygen and carbon chain.Alternatively, the alcohol 1-10 is oxidized to the ketone 1-13 asdescribed in Comprehensive Organic Transformations, by R. C. Larock,2^(nd) Edition, (1999), p. 1234ff. Preferably the alcohol 1-10 istreated with Dess-martin periodinone to give the ketone 1-13. Ketone1-13 is then reacted with an amino alkyl phosphonate 1-14 underreductive amination conditions to give the phosphonate 1-56 in which thelink is a nitrogen and carbon chain. The preparation of amines by meansof reductive amination procedures is described, for example, inComprehensive Organic Transformations, by R. C. Larock, 2^(nd) edition,p. 835. In this procedure, the amine component and the aldehydecomponent are reacted together in the presence of a reducing agent suchas, for example, borane, sodium cyanoborohydride or diisobutylaluminumhydride, to yield the amine product.

For example, the alcohol 1-10 is treated with triflate 1-15, prepared asdescribed in Tetrahedron Lett. 1986, 27, 1497, and potassium carbonatein DMF, to give the ether 1-16. Alternatively, for example, the ketone1-13 is treated with amine 1-17 (Acros) in methanol and then after aperiod of time sodium borohydride is added to give the amine 1-18. Usingthe above procedures, but employing, in place of the triflate 1-15, orthe amine 1-17, phosphonates 1-11 and 1-14, respectively, thecorresponding products 1-12 and 1-56 are obtained.

The reactions shown in Schemes 1.4-1.5 illustrate the preparation of thecompounds 1-22 in which the phosphonate is linked through a carbon chainand a heteroatom. Phenol 1-7 (Schemes 1.1-1.3) is treated with dibromide1-19 using the conditions described in Schemes 1.1-1.3 for thepreparation of 1-9 from 1-7, to give bromide 1-20. Bromide 1-20 is thentreated with the dialkyl hydroxy, thio or amino-substitutedalkylphosphonate 1-21 to give the product 1-22. The reaction isperformed in the presence of a base, in a polar aprotic solvent such asdioxan or N-methylpyrrolidinone. The base employed in the reactiondepends on the nature of the reactant 1-21. For example, if X is O, astrong base such as, for example, lithium hexamethyldisilylazide orpotassium tert. butoxide is employed. If X is S, NH or N-alkyl, aninorganic base such as cesium carbonate and the like is employed.

For example, 1-7 is treated with dibromoethane 1-23, as described inSchemes 1.1-1.3 to give the bromide 1-24. Bromide 1-24 is then treatedwith amine 1-25, prepared as described in J. Org. Chem. 2000, 65, 676,in DMF and potassium carbonate at ca 80° C. to give the phosphonate1-26. Alternatively bromide 1-24 is then heated at reflux with anequimolar amount of a dialkyl 2-mercaptoethylphosphonate 1-27, thepreparation of which is described in Aust. J. Chem., 1990, 43, 1123, inthe presence of sodium carbonate, to afford the thioether product 1-28.Using the above procedures, but employing, in place of the dibromoethane1-23, different dibromo compounds 1-19 and/or different alkylphosphonates 1-21 in place of 1-25 or 1-27, the corresponding products1-22 are obtained.

Scheme 1.6 illustrates the synthesis of target molecules 1-32, in whichA is Br, Cl, [OH], [NH], or the group link-P(O)(OR¹)₂. The preparationof 1-4 is illustrated in Scheme 1.1. Treatment of chloride 1-4 withamine 1-29 in reluxing isopropanol gives amine 1-30. The preparation of1-29 in which A is group link-P(O)(OR¹)₂ is described below in Schemes1.8-1.12. Treatment of amine 1-30 according to conditions described inU.S. Pat. No. 5,770,599 then affords the final product 1-31.

The reactions shown in Scheme 1.6 illustrate the preparation of thecompounds 1-31 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme1.7 depicts the conversion of the compounds 1-31 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 1-32. In this procedure,the compounds 1-31 are converted, using the procedures described inSchemes 1.1-1.6 into the compounds 1-32.

Schemes 1.8-1.12 describe the preparation of phosphonate-containingderivatives 1-29 which are employed in the preparation of thephosphonate ester intermediates 1-32.

Schemes 1.8-1.10 illustrates the preparation of 1-29 in which thephosphonate is attached through a heteroatom e.g. O, S, or N, and acarbon linker. In this procedure an optionally protected aniline isreacted with an alkylphosphonate 1-34 in which Lv is a leaving groupsuch as triflate, Br, Cl, Mesyl, etc, in the presence of a suitablebase. The base required for this transformation depends on the nature ofthe heteroatom X. For example, if X is N or S, an excess of an inorganicbase such as, for example, potassium carbonate, in the presence of anorganic solvent such as dimethylformamide, is suitable. The reactionproceeds at from ambient temperature to about 80° C. to afford thedisplacement products 1-35. If X is O, an equimolar amount of a strongbase, such as, for example, lithium hexamethyldisilylazide and the like,is employed, in the presence of a solvent such as tetrahydrofuran.Deprotection, of the amine group as described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, ThirdEdition (1999), chapter 7, affords the amine 1-36.

For example, the diamine 1-37 (Aldrich), protected as the CBZ carbamate(Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M.Wuts, Wiley, Third Edition (1999), page 531ff) is treated with anequimolar amount of triflate 1-38, the preparation of which is describedin Tetrahedron Lett. 1986, 27, 1497, in dimethylformamide containingexcess potassium carbonate, at about 60° C. to afford the phosphonateproduct 1-39. Deprotection by reduction over palladium on carbon in thepresence of hydrogen then affords the amine 1-40.

Alternatively, the aminophenol 1-41, protected as the CBZ carbamate asdescribed above, is reacted with one equivalent of triflate 1-38 to givephosphonate 1-42. Removal of the CBZ group by catalytic reduction overpalladium on carbon in the presence of hydrogen, as described above,then affords the amine 1-43.

Using the above procedures, but employing, in place of the aniline 1-37or phenol 1-41, different anilines 1-33, and/or differentalkylphosphonates 1-34, in place of 1-38, the corresponding products1-36 are obtained.

Schemes 1.11-1.12 illustrates the preparation of 1-29 in which thephosphonate is attached through a unsaturated or saturated carbonlinker. In this procedure, an optionally protected halo-substitutedaniline 1-44 is coupled, by means of a palladium-catalyzed Heck reactionwith a dialkyl alkenyl phosphonate 1-45, to afford the coupled product1-46. The coupling of aryl halides with olefins by means of the Heckreaction is described, for example, in Advanced Organic Chemistry, by F.A. Carey and R. J. Sundberg, Plenum, (2001), p. 503ff, and in Acc. Chem.Res., 1979, 12, 146. The aryl bromide and the olefin are coupled in apolar solvent such as dimethylformamide or dioxane, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine) palladium(0)or a palladium(II) catalyst such as palladium(II) acetate, andoptionally in the presence of a base such as triethylamine or potassiumcarbonate, to afford the coupled product 1-46. Protection of anilines isdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Third Edition (1999), chapter 7. Preferably theaniline is treated with a BOC reagent such as BOC chloride, or BOCanhydride in the presence of DMAP and a base e.g. triethylamine toafford the protected aniline. Optionally, the product 1-46 can bereduced to afford the saturated phosphonate 1-47. Methods for thereduction of carbon-carbon double bonds are described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, (1989),page 6. The methods include catalytic reduction, and chemical reduction,the latter for example employing diborane or diimide.

For example, BOC protected 3-chloro-4-fluoro aniline 1-50 (Aldrich) isreacted with a dialkyl propenyl phosphonate 1-51, the preparation ofwhich is described in J. Med. Chem., 1996, 39, 949, in the presence ofbis(triphenylphosphine) palladium(II) chloride, as described in J. Med.Chem., 1992, 35, 1371, to afford the coupled product 1-52. The BOCprotection of the aniline is performed by treating the correspondinganiline with BOC anhydride in the presence of DMAP. The product 1-52 isreduced, for example by reaction with diimide, as described in J. Org.Chem. 1965, 30, 3965, to afford the saturated product 1-53. Boc removalby treatment of 1-52 and 1-53 with TFA in THF or dioxane affords theproducts 1-54 and 1-55 respectively. Using the above procedures, butemploying, in place of the halo aniline compound 1-50, differentanilines 1-44, and/or different phosphonates 1-45 the correspondingproducts 1-48 and 1-49 are obtained.

The procedures described for the introduction of phosphonate moieties(Schemes 1.1-1.12) are, with appropriate modifications known to oneskilled in the art, transferable to different chemical substrates. Thus,the methods described above for the introduction of phosphonate groupsonto 1-12, 1-56 and 1-22 are also applicable to the introduction ofphosphonate moieties onto anilines 1-29 and vice versa.

Example 2 Preparation of Exemplary Compounds of the Present Invention

Scheme 2.1 illustrates the preparation of compounds 2-4 in which A isBr, I, [SH], [NH] etc or the group link-P(O)(OR¹)₂. The amine 2-1 isprepared as described in U.S. Pat. No. 5,521,84. Amine 2-1 is coupledwith the acid 2-2 to give the amide 2-3. The preparation of amides fromcarboxylic acids and derivatives is described, for example, in OrganicFunctional Group Preparations, by S. R. Sandier and W. Karo, AcademicPress, 1968, page 274. The carboxylic acid is reacted with the amine inthe presence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, in a non-protic solventsuch as, for example, pyridine, DMF or dichloromethane, to afford theamide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride or anhydride, and thenreacted with the amine, in the presence of an organic base such as, forexample, pyridine, to afford the amide.

The conversion of a carboxylic acid into the corresponding acid chlorideis effected by treatment of the carboxylic acid with a reagent such as,for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane. Preferably, the acid 2-2 is treatedwith oxalyl chloride in an inert solvent such as dichloromethanefollowed by the addition of a few drops of DMF and then treated with theamine 2-1 to give the amide 2-3. The acid, 2-2 is prepared according toSchemes 2.7-2.8 shown below.

The reactions shown in Scheme 2.1 illustrate the preparation of thecompounds 2-3 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme2.2 depicts the conversion of the compounds 2-3 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 2-4. In this procedure,the compounds 2-3 are converted, using the procedures described below,Schemes 2.7-2.12, into the compounds 2-4.

Scheme 2.3 illustrates the preparation of compounds 2-6 in which A isBr, I, [SH], [NH], etc., or the group link-P(O)(OR¹)₂. The amine 2-1 istreated with acid 2-5 as described above, Scheme 2.1, to give the amide2-6. The preparation of acid 2-5 is described in Schemes 2.9-2.10 below.

The reactions shown in Scheme 2.3 illustrate the preparation of thecompounds 2-6 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br, etc. Scheme2.4 depicts the conversion of the compounds 2-6 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 2-7. In this procedure,the compounds 2-6 are converted, using the procedures described below,Schemes 2.7-2.12, into the compounds 2-7.

Schemes 2.5-2.6 illustrates the preparation of compounds 2-10 in which Ais Br, I, [SH], [NH], etc., or the group link-P(O)(OR¹)₂. The amine 2-1is treated with acid 2-8 as described above, Scheme 2.1, to give theamide 2-9. The preparation of acid 2-8 is described in Schemes 2.11-2.12below.

The reactions shown in Schemes 2.5-2.6 illustrate the preparation of thecompounds 2-9 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br, etc. Scheme2.6 depicts the conversion of the compounds 2-9 in which A is [OH],[SH], [NH], Br, etc., into the phosphonate esters 2-10. In thisprocedure, the compounds 2-9 are converted, using the proceduresdescribed below, Schemes 2.7-2.12, into the compounds 2-10.

Schemes 2.7-2.8 describe the preparation of phosphonate-containingderivatives 2-2, in which A is Br, Cl, [OH], [NH], or the grouplink-P(O)(OR¹)₂ that are employed in the preparation of the phosphonateester intermediates 2-4. Piperazine 2-11 is protected with a BOC groupaccording to methods described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999) p. 518ff. Preferably piperazine is treated with 1 equivalent ofBOC anhydride in methanol or DMF and one equivalent of triethylamine togive the BOC amine 2-12. Treatment of 2-12 with an alkylphosphonate 2-13in which Lv is a leaving group such as triflate, Br, Cl, Mesyl, etc., inthe presence of a suitable base, affords the product 2-14. The baserequired for this transformation is typically an inorganic base such as,for example, potassium carbonate, in the presence of an organic solventsuch as dimethylformamide. The reaction proceeds at from ambienttemperature to about 80° C. to afford the displacement products 2-14.Deprotection, of the BOC-amine group as described in Protective Groupsin Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, ThirdEdition (1999) p 520ff., affords the amine 2-15. The amine 2-15 is thenreacted with the acid 2-16 (Aldrich) in the presence of a base to givethe product acid 2-17. For example, 2-12 prepared from piperazine asdescribed above, is treated with bromophosphonate 2-18, prepared asdescribed in Syn. 1999, 9, 909, and potassium carbonate in THF to givethe amine 2-19. The BOC amine 2-19 is then deprotected by treatment withtrifluoroacetic acid in dichloromethane to give the amine 2-20. Theamine 2-20 is then reacted with the bromomethyl benzoic acid 2-16 in THFor dioxane in the presence of triethylamine, or aqueous potassiumcarbonate, to give the acid 2-21. Using the above procedures, butemploying, in place of the bromo phosphonate compound 2-18, differentphosphonates 2-13, the corresponding products 2-17 are obtained.

Schemes 2.9-2.10 describes the preparation of acids 2-5 in which thephosphonate is attached to the scaffold through a heteroatom and carbonlinker. The benzyl protected ketone 2-22, prepared from thecorresponding acid by treatment with benzyl alcohol in the presence ofDCC and DMAP in DMF, as described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999), p. 373ff., is treated with a brominating agent to give the bromoketone 2-23. Protection of the ketone as the cyclic dioxalone asdescribed in T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999), p. 312ff., gives 2-24. Dioxalone 2-24 is then treated with thedialkyl hydroxy, thio or amino-substituted alkylphosphonate 2-25 to givethe dioxalone 2-26. The reaction is performed in the presence of a base,in a polar aprotic solvent such as dioxane or N-methylpyrrolidinone. Thebase employed in the reaction depends on the nature of the reactant2-25.

For example, if X is O, a strong base such as, for example, lithiumhexamethyldisilylazide or potassium tert. butoxide is employed. If X isS, NH or N-alkyl, an inorganic base such as cesium carbonate and thelike is employed. Deprotection of the dioxalone as described in T. W.Greene and P. G. M. Wuts, Wiley, Third Edition (1999), p. 317ff., givesketone 2-27 which is then treated under reductive amination conditionswith N-methyl piperazine to give the amine 2-28. The preparation ofamines by means of reductive amination procedures is described, forexample, in Comprehensive Organic Transformations, by R. C. Larock,2^(nd) edition, p. 835. In this procedure, the amine component and thealdehyde component are reacted together in the presence of a reducingagent such as, for example, borane, sodium cyanoborohydride ordiisobutylaluminum hydride, to yield the amine product. Deprotection ofthe ester group as described in T. W. Greene and P. G. M. Wuts, Wiley,Third Edition (1999) p. 373ff then affords the acid 2-29.

For example, 4-acetyl benzoic acid is treated with benzyl bromide in thepresence of potassium carbonate in aqueous THF to give the ester 2-22.Treatment of the ester 2-22 with bromine in acetic acid, or NBS and AIBNin CCl₄ affords the bromide 2-23. Bromide 2-23 is then reacted with1,2-ethane diol in toluene at reflux under a dean stark head with acatalytic amount of p-TsOH present to give the dioxalone 2-24. Dioxalone2-24 is reacted with dialkyl 2-aminoethyl phosphonate 2-30, prepared asdescribed in J. Org. Chem., 2000, 65, 676, in dimethylformamide at about80° C., in the presence of potassium carbonate, to afford the amine2-31. Treatment of the dioxalone 2-31 with 1N hydrochloric acid in THFthen yields the ketone 2-32. Ketone 2-32 is reacted with N-methylpiperazine in the presence of triethylamine followed 30 minutes later bythe addition of sodiumcyano borohydride to give the amine 2-33. Removalof the benzyl ester by hydrolysis using sodium hydroxide in aqueous THFgives the acid 2-34. Using the above procedures, but employing, in placeof the amino phosphonate compound 2-30, different phosphonates 2-25, thecorresponding products 2-29 are obtained.

Schemes 2.11-2.12 illustrates the preparation of acid 2-8 in which thephosphonate is attached through a unsaturated or saturated carbonlinker. In this procedure, the acid 2-16 (Aldrich) is treated withN-methyl piperazine as described in Schemes 2.7-2.8 for the preparationof 2-17, to give the acid 2-35. Acid 2-35 is then brominated withbromine or NBS to give the bromide 2-36. Bromide 2-36 is optionallyprotected as the benzyl or t-butyl ester, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Third Edition (1999), page 373ff., to give 2-37. Ester 2-37 is thencoupled, by means of a palladium-catalyzed Heck reaction with a dialkylalkenyl phosphonate 2-38, to afford the coupled product 2-39. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, (2001), p. 503ff., and in Acc. Chem. Res.,1979, 12, 146. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxane, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine) palladium(0)or a palladium(II) catalyst such as palladium(II) acetate, andoptionally in the presence of a base such as triethylamine or potassiumcarbonate, to afford the coupled product 2-39. Optionally, the product2-39 can be reduced to afford the saturated phosphonate 2-40. Methodsfor the reduction of carbon-carbon double bonds are described, forexample, in Comprehensive Organic Transformations, by R. C. Larock, VCH,(1989), page 6. The methods include catalytic reduction, and chemicalreduction, the latter for example employing diborane or diimide.

For example, amine 2-35 is then treated with NBS and AIBN in carbontetrachloromethane at reflux to give the bromide 2-43. Bromide 2-43 isthen reacted in t-butanol with DCC and DMAP to give the t-butyl ester2-44. Ester 2-44 is then reacted with dialkyl propenyl phosphonate 2-45,the preparation of which is described in J. Med. Chem., 1996, 39, 949,in the presence of bis(triphenylphosphine) palladium(II) chloride, asdescribed in J. Med. Chem., 1992, 35, 1371, to afford the coupledproduct 2-46. This product 2-46 is then treated with aqueous HCl indioxane to give the acid 2-48. Optionally, the alkene 2-46 can bereduced by reaction with diimide, as described in J. Org. Chem., 1965,30, 3965, to afford the saturated product 2-47. Hydrolysis of the esteras described above through treatment with aqueous HCl in dioxane givesthe acid 2-49. Using the above procedures, but employing, in place ofthe phosphonate compound 2-45, different phosphonates 2-38, thecorresponding products 2-41 and 2-42 are obtained.

Example 3 Exemplary Compounds of the Present Invention

Scheme 3.1 illustrates exemplary compounds of the present invention,wherein the phosphonate group can either be linked through a carbonatom, or a heteroatom, respectively.

Schemes 3.2-3.3 illustrates the synthesis of target molecules of type3-11, in which A is Br, Cl, [OH], [NH], or the group link-P(O)(OR¹)₂.The preparation of 3-4, in which is A is a phosphonate is describedbelow. Conversion of 3-4 into 3-9 in which A is methoxymethyl isdescribed in EP 0817775 B1 and similar conditions can be used to prepare3-9 in which A is the group link-P(O)(OR¹)₂. Nitration of the diether3-4 gives nitro compound 3-5, which, followed by reduction understandard reducing conditions as described in Comprehensive OrganicTransformations, by R. C. Larock, 2^(nd) Edition, (1999), p 821.,affords the amine 3-6.

For example, 3-4 is treated with cold nitric acid in acetic acid,followed by catalytic hydrogenolysis of the nitro product in acidicethanol over platinum oxide at high pressure to give the amine 3-6. Thehydrochloride salt that is isolated is then heated at about 160° C. withammonium formate and formamide to generate the quinazoline 3-7. Thequianzoline is converted to the chloride, 3-8, as described in EP0817775 B1. Preferably, the quinazoline, 3-7, is treated with oxalylchloride in chloroform and DMF to give the chloride 3-8. Displacement ofthe chloride by the amine, 3-10, then affords the product 3-9. Forexample, heating the chloride 3-8 with 3-ethynyl-aniline in isopropanolat reflux gives 3-9.

The reactions shown in Scheme 3.2 illustrate the preparation of thecompounds 3-9 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br, etc. Scheme3.3 depicts the conversion of the compounds 3-9 in which A is [OH],[SH], [NH], Br, etc., into the phosphonate esters 3-11. In thisprocedure, the compounds 3-9 are converted, using the proceduresdescribed below, Schemes 3.10-3.21, into the compounds 3-11.

Schemes 3.4-3.5 illustrates the synthesis of target molecules of type3-14, in which A is Br, Cl, [OH], [NH], or the group link-P(O)(OR¹)₂.Conversion of 3-12 into 3-13 is completed using the conditions describedabove, Scheme 3.2, for the conversion of 3-4 into 3-9. The preparationof 3-12, in which is A is a phosphonate is described below in Schemes3.14-3.17.

The reaction shown in Scheme 3.4 illustrates the preparation of thecompounds 3-13 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme3.5 depicts the conversion of the compounds 3-13 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 3-14. In this procedure,the compounds 3-13 are converted, using the procedures described below,Schemes 3.10-3.13, into the compounds 3-14.

Schemes 3.6-3.7 illustrates the synthesis of target molecules of type3-20, in which A is Br, Cl, [OH], [NH], or the group link-P(O)(OR¹)₂.The preparation of 3-15 is described in EP 0817775 B1. Diether 3-15 isconverted to the chloride 3-16 using conditions described in EP 0817775B1 or as described above, Scheme 3.2. Treatment of chloride 3-16 withamine 3-18, in reluxing isopropanol gives 3-17. The preparation of 3-18,in which A is group link-P(O)(OR¹)₂ is shown below in Schemes 3.18-3.19.

The reactions shown in Scheme 3.6 illustrate the preparation of thecompounds 3-17 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme3.7 depicts the conversion of the compounds 3-17 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 3-20. In this procedure,the compounds 3-17 are converted, using the procedures described below,Schemes 3.10-3.21, into the compounds 3-20.

Schemes 3.8-3.9 illustrate the synthesis of target molecules of type3-24, in which A is Br, Cl, [OH], [NH], or the group link-P(O)(OR¹)₂.The preparation of 3-16 is described in Scheme 3.6. Chloride 3-16 isconverted to the amine 3-23 by treatment with amine 3-22 in refluxingisopropanol. The preparation of 3-22 in which A is group link-P(O)(OR¹)₂is shown below in Schemes 3.20-3.21.

The reaction shown in Scheme 3.8 illustrates the preparation of thecompounds 3-23 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br, etc. Scheme3.9 depicts the conversion of the compounds 3-23 in which A is [OH],[SH], [NH], Br, etc., into the phosphonate esters 3-24. In thisprocedure, the compounds 3-23 are converted, using the proceduresdescribed below in Schemes 3.10-3.21, into the compounds 3-24.

Schemes 3.10-3.13 describe the preparation of phosphonate-containingderivatives 3-19, 3-30, 3-69, 3-70 which are employed in the preparationof the phosphonate ester intermediates 3-11 (Scheme 3.3). Thedihydroxybenzoic acid 3-25 is treated with one equivalent of thephosphonate alkylating agent, in which Lv is a leaving group such asmesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in the presenceof base as described in EP 0817775 B1, to give the ether 3-26. The etheris then subjected to the same alkylating conditions in the presence of2-bromoethylmethyl ether (Aldrich) to give the diethers 3-19, 3-30,3-69, and 3-70. For example, ester 3-25, prepared from the correspondingacid (Aldrich) by refluxing in concentrated HCl and ethanol in acetone,is treated with dialkyl 4-bromobutylphosphonate 3-28, prepared asdescribed in Syn. 1999, 9, 909, potassium carbonate andtetrabutylammonium iodide to give the ether 3-29. Ether 3-29 is thentreated with 2-bromoethylmethyl ether (Aldrich), potassium carbonate andtetrabutyl ammonium iodide to give the diether 3-30. Using the aboveprocedures, but employing, in place of the bromobutylphosphonate 3-28,different phosphonates 3-27, and 3-37, the corresponding products 3-4,3-19, 3-69, 3-70 are obtained.

Schemes 3.12-3.13 also describe the preparation ofphosphonate-containing derivatives 3-69, 3-70 which are employed in thepreparation of the phosphonate ester intermediates 3-11 (Scheme 3.3).The dihydroxybenzoic acid 3-25, is treated with one equivalent ofalcohol 3-31, as described in Schemes 3.10-3.11 to give ether 3-32. Thisether 3-32 is then further treated with one equivalent of2-bromoethylmethyl ether (Aldrich), and one equivalent of base asdescribed in Schemes 3.10-3.11, to give the diether 3-33. Treatment withan phosphonate alkylating agent 3-27, in which Lv is a group such asmesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in the presenceof base then affords ether 3-69.

For example, 3-25 in acetone is treated with 2-bromoethanol, asdescribed above in Scheme 3.10 for the preparation of 3-26 from 3-25, togive 3-35. Reaction with 2-bromoethylmethyl ether (Aldrich), and oneequivalent of sodium hydride in DMF, then affords the diether 3-36.Reaction of diether 3-36 with triflate 3-37, prepared as described inTetrahedron Lett. 1986, 27, 1497, and potassium carbonate in DMF, givesthe ether 3-70. Using the above procedures, but employing, in place ofthe bromobutylphosphonate 3-28, different phosphonates 3-27, and inplace of alcohol 3-34, different alcohols 3-31, the correspondingproducts 3-69 are obtained.

Schemes 3.14-3.17 describe the preparation of phosphonate-containingderivatives 3-12, 3-75, 3-76 which are employed in the preparation ofthe phosphonate ester intermediates 3-14 (Scheme 3.5).

The dihydroxybenzoic acid 3-25 is first treated with 2-bromoethylmethylether (Aldrich), as described in Schemes 3.10-3.11 to give the ether3-38. Ether 3-38 is then treated with one equivalent of the phosphonatealkylating agent, in which Lv is a group such as mesyl,trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in the presence ofbase, as described in EP 0817775 B1, to give the ether 3-75. Forexample, ether 3-38 is treated with triflate 3-37, prepared as describedin Tetrahedron Lett. 1986, 27, 1497, and potassium carbonate in DMF, togive the ether 3-39. Using the above procedures, but employing, in placeof the phosphonate 3-37, different phosphonates 3-27, the correspondingproducts 3-75 are obtained.

Schemes 3.16-3.17 describe the preparation of phosphonate-containingderivatives 3-76 which are employed in the preparation of thephosphonate ester intermediates 3-13 (Scheme 3.4). Ether 3-38 (Schemes3.14-3.15) is reacted with 2-bromoethanol, as described above, Schemes3.13, for the preparation of 3-35 from 3-25, to give 3-40. Treatment ofdiether 3-40 with an phosphonate alkylating agent 3-27, in which Lv is agroup such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc.,in the presence of base then affords ether 3-76. For example, 3-38 inacetone is treated 2-iodoethanol, 3-66, as described above, Schemes3.13, for the preparation of 3-35 from 3-25, to give 3-41. Reaction withbromobutylphosphonate 3-28, as described above (Schemes 3.10-3.11) thenaffords 3-42. Using the above procedures, but employing, in place of thebromobutylphosphonate 3-28, different phosphonates 3-27, and in place ofalcohol 3-66, different alcohols 3-63, the corresponding products 3-76are obtained.

Schemes 3.18-3.19 describe the preparation of phosphonate-containingderivatives, which are employed in the preparation of the phosphonateester intermediates 3-20 (Schemes 3.6-3.7). Aniline 3-43 is firstprotected using methods described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999), chapter 7. Bromination of 3-44 by treatment with bromine inacetic acid or NBS in tetrachloromethane at reflux, in the presence ofAIBN then affords the bromophenol 3-45. Alkylation with a phosphonatealkylating agent 3-77 as described above, Schemes 3.10-3.11, thenaffords the phosphonate 3-46. Coupling with TMS acetylene by palladiummediated reaction affords the alkyne 3-47 which can then be deprotectedusing conditions described in Protective Groups in Organic Synthesis, byT. W. Greene and P. G. M. Wuts, Wiley, Third Edition (1999), chapter 7,gives the amine 3-48. The coupling of aryl halides with alkynes isdescribed, for example, in Comprehensive Organic Synthesis, Eds. Trostand Fleming, Oxford, (1991), 3, part 2.4, page 521.

For example, 3-aminophenol, 3-49, is treated with one equivalent ofmesyl chloride in the presence of pyridine to afford 3-50. The mesylcompound 3-50 is then treated with bromine in acetic acid to give thebromide 3-51. Bromide 3-51 is alkylated with 3-37 as described above(Schemes 3.12-3.13) to give the phosphonate 3-52. Treatment of 3-52 withTMS-acetylene in a polar solvent such as dimethylformamide oracetonitrile, in the presence of a palladium(0) catalyst such astetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalystsuch as palladium(I) acetate, and optionally in the presence of a basesuch as triethylamine or potassium carbonate and copper (I) iodide,affords the coupled product 3-53. Deprotection of the mesyl group bytreatment with potassium hydroxide in THF and water gives the amine3-54. Using the above procedures, but employing, in place of thephosphonate 3-37, different phosphonates 3-77, and in place of alcohol3-49, different alcohols 3-43, the corresponding products 3-48 areobtained.

Schemes 3.20-3.21 describes the preparation of phosphonate-containingderivatives 3-58, which are employed in the preparation of thephosphonate ester intermediates 3-24 (Scheme 3.9). 3-Iodoaniline isfirst protected using methods described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999), chapter 7. Coupling with propargyl alcohol by palladium mediatedreaction, as described above (Schemes 3.18-3.19) affords the alkyne3-56. Alkylation with a phosphonate alkylating agent 3-27 as describedabove, Schemes 3.10-3.11, then affords the phosphonate 3-57. Finally,deprotection using conditions described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999), chapter 7, gives the amine 3-58.

For example, 3-iodoaniline (Aldrich) is treated with BOC anhydride inthe presence of pyridine and DMAP to afford 3-59. Treatment of 3-59 withpropargyl alcohol in a polar solvent such as dimethylformamide oracetonitrile, in the presence of a palladium(0) catalyst such astetrakis(triphenylphosphine) palladium(0) or a palladium(II) catalystsuch as palladium(II) acetate, and optionally in the presence of a basesuch as triethylamine or potassium carbonate and copper (I) iodide,affords the coupled product 3-60. Alkylation of 3-60 with triflate 3-37,as described above, Schemes 3.12-3.13, then affords the phosphonate3-61. Deprotection of the BOC group by treatment with TFA in THF ordioxane gives the amine 3-62. Using the above procedures, but employing,in place of the phosphonate 3-37, different phosphonates 3-27, and inplace of iodoaniline 3-59, different anilines, 3-55, the correspondingproducts 3-58 are obtained.

The procedures described for the introduction of phosphonate moieties(Schemes 3.10-3.21) are, with appropriate modifications known to oneskilled in the art, transferable to different chemical substrates. Thus,for example, the methods described above for the introduction ofphosphonate groups onto the aryl rings of 3-18 and 3-48, are alsoapplicable to the introduction of phosphonate moieties onto the alkynes3-22 and 3-58, and vice versa.

Example 4 Exemplary Compounds of the Present Invention

Scheme 4.1 illustrates the preparation of compounds 4-52 in which A isBr, I, [SH], [NH], etc., or the group link-P(O)(OR¹)₂. The preparationof these compounds follows procedures described in J. Med. Chem. 2000,43, 12, 2310. The phthalic anhydride 4-1 is melted with a methylpyridine4-2 in which A is Br, I, [SH], [NH], etc., or the group link-P(O)(OR¹)₂,under high temperature to give 4-3. The synthesis of 4-2 is describedbelow. The product 4-3 on treatment with hydrazine in water andoptionally ethanol, then rearranges to afford the ketone 4-4. Ketone 4-4is then converted to the chloride 4-5 by treatment with a phosphorousoxychloride in an inert solvent such as acetonitrile at about 50° C. Theamine, 4-7, is introduced by heating the chloride 4-5 in the presence ofthe amine, optionally in a high boiling solvent such as xylenes or DMFto give the amine 4-6. Alternatively the pyridinone 4-4 can be directlyconverted to the product 4-6 in a one step procedure involving meltingthe aniline, 4-7, with the pyridinone in the presence of a dehydratingagent such as phosphorus pentoxide as described in J. Med. Chem. 2000,43, 12, 2310.

The reactions shown in Scheme 4.1 illustrate the preparation of thecompounds 4-6 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme4.2 depicts the conversion of the compounds 4-6 in which A is [OH],[SH], [NH], Br, etc., into the phosphonate esters 4-52. In thisprocedure, the compounds 4-6 are converted, using the proceduresdescribed below, Schemes 4.5-4.15, into the compounds 4-52.

Scheme 4.3 illustrates the preparation of compounds 4-12 in which A isBr, I, [SH], [NH], etc., or the group link-P(O)(OR¹)₂. The chloride 4-8,described in J. Med. Chem. 2000, 43, 12, 2310, is treated with ananiline 4-9, in which A is Br, I, [SH], [NH], etc., or the grouplink-P(O)(OR¹)₂, as described above in Scheme 4.1, to give amine 4-10.Alternatively the pyridinone 4-11, described in J. Med. Chem. 2000, 43,12, p 2310 is treated with an aniline 4-9 in which A is Br, I, [SH],[NH] etc or the group link-P(O)(OR¹)₂ as described above, Scheme 4.1, togive amine 4-10.

The reactions shown in Scheme 4.3 illustrate the preparation of thecompounds 4-10 in which the substituent A is either the grouplink-P(O)(OR¹)₂ or a precursor such as [OH], [SH], [NH], Br etc. Scheme4.4 depicts the conversion of the compounds 4-10 in which A is [OH],[SH], [NH], Br etc, into the phosphonate esters 4-12. In this procedure,the compounds 4-10 are converted, using the procedures described below,Schemes 4.5-4.15, into the compounds 4-12.

Schemes 4.5-4.10 describe the preparation of phosphonate-containingderivatives 4-2, in which A is Br, Cl, [OH], [NH], and the grouplink-P(O)(OR¹)₂, which are employed in the preparation of thephosphonate ester intermediates 4-52.

Schemes 4.5-4.6 describes the preparation of 4-2 (Scheme 4.1) in whichthe phosphonate is attached directly to the ring. The halo pyridine 4-13is treated with a dialkyl phosphite 4-14 to give the phosphonate 4-15.The coupling reaction is conducted in the presence of a palladium (0)catalyst, for example as described in J. Med. Chem., 1992, 35, 1371. Forexample 2-bromo-4-methyl pyridine (Aldrich) 4-16 is reacted with anequimolar amount of a dialkyl sodium phosphite 4-14a, in the presence oftetrakis(triphenylphosphine)palladium(0) and triethylamine, in tolueneat reflux, to yield the phosphonate 4-17. Using the above procedures,but employing, in place of the halo pyridine compound 4-16, differentpyridines 4-13, and/or different dialkyl sodium phosphites 4-14 thecorresponding products 4-15 are obtained.

Schemes 4.7-4.8 illustrates the preparation of 4-2 in which thephosphonate is attached through a unsaturated or saturated carbonlinker. In this procedure, a halo-substituted pyridine 4-13 is coupled,by means of a palladium-catalyzed Heck reaction with a dialkyl alkenylphosphonate 4-18. The coupling of aryl halides with olefins by means ofthe Heck reaction is described, for example, in Advanced OrganicChemistry, by F. A. Carey and R. J. Sundberg, Plenum, (2001), p. 503ff.,and in Acc. Chem. Res., 1979, 12, 146. The aryl bromide and the olefinare coupled in a polar solvent such as dimethylformamide or dioxane, inthe presence of a palladium(0) catalyst such astetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalystsuch as palladium(II) acetate, and optionally in the presence of a basesuch as triethylamine or potassium carbonate, to afford the coupledproduct 4-19. Optionally, the product 4-19 can be reduced to afford thesaturated phosphonate 4-20. Methods for the reduction of carbon-carbondouble bonds are described, for example, in Comprehensive OrganicTransformations, by R. C. Larock, VCH, (1989), p. 6. The methods includecatalytic reduction, and chemical reduction, the latter for exampleemploying diborane or diimide.

For example, 2-bromo-4-methylpyridine 4-16 is reacted with a dialkylbutenyl phosphonate 4-21, the preparation of which is described in J.Med. Chem., 1996, 39, 949, in the presence of bis(triphenylphosphine)palladium(II) chloride, as described in J. Med. Chem., 1992, 35, 1371,to afford the coupled product 4-22. Optionally, the product 4-22 isreduced, for example by reaction with diimide, as described in J. Org.Chem., 1965, 30, 3965, to afford the saturated product 4-23. Using theabove procedures, but employing, in place of the halo pyridine compound4-16, different pyridines 4-13, and/or different phosphonates 4-18 thecorresponding products 4-19 and 4-20 are obtained.

Schemes 4.9-4.10 illustrates the preparation of 4-2 in which thephosphonate is attached through a heteroatom e.g. O, S or N, and acarbon chain. In this procedure, a halo-substituted pyridine 4-13 isreacted with a dialkyl hydroxy- or thio-alkylphosphonate 4-24. Thepreparation of alkoxypyridines by the reaction of alkoxides withhalopyridines is described, for example, in J. Am. Chem. Soc., 1960, 82,4414. The preparation of pyridine thioethers by reaction ofhalopyridines with thiols is described, for example, in Chemistry ofHeterocyclic Compounds, Pyridine and its derivatives, E. Klingsberg,Ed., part 4, page 358. The alcohols and thiols are transformed intometal salts, for example sodium or potassium salts, and then reactedwith the halopyridine substrates at elevated temperatures, optionally inthe presence of copper powder catalyst, to afford the ether or thioetherproducts 4-25. For example, a tetrahydrofuran solution of3-bromo-4-methylpyridine 4-26 (Aldrich) is heated at reflux with anequimolar amount of a dialkyl 2-mercaptoethylphosphonate 4-27, thepreparation of which is described in Aust. J. Chem., 43, 1123, (1990),in the presence of sodium carbonate, to afford the thioether product4-28. Using the above procedures, but employing, in place of thehalopyridines 4-26, different halopyridines 4-13, and/or differenthydroxy or thio-alkyl phosphonates 4-24, the corresponding products 4-25are obtained.

Schemes 4.11-4.15 describe the preparation of phosphonate-containingderivatives 4-10, in which A is Br, Cl, [OH], [NH], and the grouplink-P(O)(OR¹)₂ which are employed in the preparation of the phosphonateester intermediates 4-12 (Schemes 4.3-4.4).

Schemes 4.11-4.13 illustrates the preparation of 4-9 (Scheme 4.3) inwhich the phosphonate is attached through a heteroatom e.g. O, S, or N,and a carbon linker. In this procedure an optionally protected anilineis reacted with an alkylphosphonate 4-30 in which Lv is a leaving groupsuch as triflate, Br, Cl, Mesyl, etc, in the presence of a suitablebase. The base required for this transformation depends on the nature ofthe heteroatom X. For example, if X is N or S, an excess of an inorganicbase such as, for example, potassium carbonate, in the presence of anorganic solvent such as dimethylformamide, is suitable. The reactionproceeds at from ambient temperature to about 80° C. to afford thedisplacement products 4-31. If X is O, an equimolar amount of a strongbase, such as, for example, lithium hexamethyldisilylazide and the like,is employed, in the presence of a solvent such as tetrahydrofuran.Deprotection, of the amine group as described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, ThirdEdition (1999) chapter 7, then affords the amine 4-32.

For example, the diamine 4-33 (Aldrich), mono-protected as the CBZcarbamate as described in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Third Edition (1999), 531 ff, istreated with an equimolar amount of triflate 4-34, the preparation ofwhich is described in Tetrahedron Lett. 1986, 27, 1497, indimethylformamide containing excess potassium carbonate, at ca 60° C. toafford the phosphonate product 4-35. Deprotection by reduction overpalladium on carbon in the presence of hydrogen then affords the amine4-36. Using the above procedures, but employing, in place of the aniline4-33, different anilines 4-29, and/or different alkylphosphonates 4-30,the corresponding products 4-32 are obtained.

Alternatively, the aminophenol 4-37, protected as the CBZ carbamate asdescribed above, is reacted with one equivalent of an alkylphosphonate4-34, as described above, to give phosphonate 4-38. Removal of the CBZgroup by catalytic reduction over palladium on carbon in the presence ofhydrogen then affords the amine 4-39.

Schemes 4.14-4.15 illustrates the preparation of 4-9 in which thephosphonate is attached through a unsaturated or saturated carbonlinker. In this procedure, an optionally protected halo-substitutedaniline 4-40 is coupled, by means of a palladium-catalyzed Heck reactionwith a dialkyl alkenyl phosphonate 4-18, as described above (Schemes4.7-4.8), to afford the coupled product 4-41. Protection of anilines isdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Third Edition (1999), chapter 7. Preferably theaniline is treated with a BOC reagent such as BOC chloride, or BOCanhydride in the presence of DMAP and a base, e.g., triethylamine, toafford the protected aniline.

Optionally, the coupled product 4-41 can be reduced, as described above(Schemes 4.7-4.8) to afford the saturated phosphonate 4-42. Removal ofthe protecting groups, as described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Third Edition(1999) chapter 7, affords the anilines 4-43 and 4-44.

For example, BOC protected 3-bromo-4-fluoro aniline 4-45 (Aldrich) isreacted with a dialkyl propenyl phosphonate 4-46, the preparation ofwhich is described in J. Med. Chem., 1996, 39, 949, in the presence ofbis(triphenylphosphine) palladium(II) chloride, as described in J. Med.Chem., 1992, 35, 1371, to afford the coupled product 4-47. The BOCprotection of the aniline is performed by treating the aniline with BOCanhydride in the presence of DMAP. The product 4-47 is reduced, forexample by reaction with diimide, as described in J. Org. Chem., 1965,30, 3965, to afford the saturated product 4-48. Treatment of 4-47 and4-48 with TFA in THF or dioxane, affords the products 4-49 and 4-50respectively. Using the above procedures, but employing, in place of thehalo pyridine compound 4-45, different pyridines 4-40, and/or differentphosphonates 4-18 the corresponding products 4-43 and 4-44 are obtained.

The procedures described for the introduction of phosphonate moieties(Schemes 4.5-4.15) are, with appropriate modifications known to oneskilled in the art, transferable to different chemical substrates. Thus,the methods described above for the introduction of phosphonate groupsonto the pyridyl ring of 4-2 are applicable to the introduction ofphosphonate moieties onto the aniline 4-9 and the reverse is also true.

Example 5 Preparation of Exemplary Compounds of the Present Invention

The desired phosphonate substituted analogs for conversion into theprodrugs are prepared by reaction of arabinofuranosylcytosine, 5-1(obtained as described in U.S. Pat. No. 3,116,282, col. 26 line 65 tocol. 28 line 25) with the respective alkylating reagents, 5-2. Schemes5.1-5.2 shows the preparation of phosphonate linkage to 5-1 through the5′ hydroxyl group. Triol 5-1 is dissolved in a solvent such as DMF, THFand is treated with a phosphonate reagent bearing a leaving group, forexample, bromine, mesyl, tosyl, or trifluoromethanesulfonyl in thepresence of a suitable organic or inorganic base.

For example, 5-1 dissolved in DMF, is treated with 8 equivalents ofsodium hydride and two equivalents of(toluene-4-sulfonylmethyl)-phosphonic acid diethyl ester 5-5, preparedaccording to the procedures in J. Org. Chem. 1996, 61, 7697, to givephosphonate 5-6 in which the linkage is a methylene group. Using theabove procedure but employing different phosphonate reagents 5-2 inplace of 5-5 the corresponding products 5-3 bearing different linkinggroups are obtained.

The desired phosphonate substituted analogs for conversion into theprodrugs are prepared by first reacting glycal 5-7 (obtained asdescribed in J. Am. Chem. Soc. 1972, 94, 3213) with phenylselenylchloride followed by treatment with the respective phosphonate alcohols5-8 in the presence of silver perchlorate (J. Org. Chem. 1991, 56,2642-2647). Oxidation of the resulting chloride using hydrogen peroxidefollowed by dihydroxylation of the resulting double bond with MCPBA andwater generates the anti-diol (Synth. Commun. 1989, 19, 1939) which uponaminolysis of uracil using triazole, 2-chlorophenyldichlorophosphate,pyridine and ammonia (Bioorg. Med. Chem. Lett. 1997, 7, 2567) providesthe desired product 5-3. Alternatively, the anti-diol can be accessedthrough an osmium tetroxide oxidation followed by selective protectionand inversion using Mitsunobu conditions.

Schemes 5.3-5.4 show the introduction of different phosphonate linkages.For example, 5-7 dissolved in CH₂Cl₂, is treated with one equivalent ofphenyl selenyl chloride at −70° C. followed by silver perchlorate in thepresence of diethyl(hydroxymethyl) phosphonate to generate 5-12. Thephosphonate is transformed into the desired analog by first oxidationwith hydrogen peroxide, followed by an MCPBA oxidation and finallyconversion of uracil to cytosine to the desired product 5-13. Using theabove procedure but employing different phosphonate reagents 5-8 inplace of 5-11 the corresponding products 5-10 bearing different linkinggroups are obtained. In some cases conversions to desired prodrugs mayrequire the use of suitable protecting groups for the amino group ofcytosine as well as the diol. Other bases could also be used to generatesimilar analogs of both 5-3 and 5-10 classes.

Example 6 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of the invention can be prepared as illustratedabove. The desired phosphonate substituted analogs are prepared byreaction of intermediate 6-5 (obtained as described in U.S. Pat. No.5,464,826) with the respective alkylating reagents 6-6. Illustratedabove is the preparation of phosphonate linkage to2′2′-difluoronucleosides through the 5′-hydroxyl group. Theappropriately protected base as described in U.S. Pat. No. 5,464,826 isdissolved in a solvent such as DMF, THF and is treated with aphosphonate reagent bearing a leaving group, for example, bromine,mesyl, tosyl, or trifluoromethanesulfonyl in the presence of a suitableorganic or inorganic base.

For instance, 6-1 (obtained as described in U.S. Pat. No. 5,464,826)dissolved in DMF, is treated with two equivalents of sodium hydride andone equivalent of (toluene-4-sulfonylmethyl)-phosphonic acid diethylester 6-8, prepared according to the procedures in J. Org. Chem. 1996,61, 7697, to give the corresponding phosphonate 6-9 in which the linkageis a methylene group. Using the above procedure but employing differentphosphonate reagents 6-6 in place of 6-8 the corresponding products 6-2bearing different linking groups are obtained.

Example 7 Preparation of Exemplary Compounds of the Present Invention

Compound 7-3 (X=—CH₂CH₂—) is prepared as outlined in Scheme 7.1.Camptosar (U.S. Pat. No. 4,604,463) is activated with p-nitrophenylchloroformate in DMF and triethyl amine, followed by reaction with anaminophosphonate to furnish compound 7-3.

Compound 7-4 is obtained by a published procedure (J. Chem. Soc. PerkinTrans. 2, 1972, 2035). Activation of the 110-OH of 7-4, followed byreaction with amine 7-21 (as its acid chloride) gives 7-5 (U.S. Pat. No.4,604,463). Compound 7-6 is prepared by refluxing 7-5 and anaminoethylphosphonate in DMF and DIPEA.

A key intermediate is 7-hydroxymethyl-10-hydroxycamptothecin 7-7, whichis prepared according to Dallavele, S. et al. (J. Med. Chem. 2000, 43,3963-3969). 7-Aldehyde derivative 7-10 is prepared by refluxing 7-7 inglacial acetic acid. Further oxidation of 7-10 gives acid 7-11. Treating7-10 with triphenylphosphoranylidene acetaldehyde, andt-butoxycarbonylmethylene triphenylphosphorane gives 7-12 and 7-13,respectively. (J. Med. Chem. 2000, 43, 3963).

Compound 7-7 is reacted with 7-22 (U.S. Pat. No. 4,604,463), followedreaction with a triflated phosphonate and NaH, to give compound 7-8.

Syntheses of 7-19, 7-18, 7-17, and 7-16 are illustrated in Scheme 7.5.Aldehyde 7-10, acid 7-11, extended aldehyde 7-12, and ester 7-13(compounds 7-14) are reacted with 7-22 to furnish 7-15a, 7-15b, 7-15c,and 7-15d. Compound 7-19 is prepared by reductive amination of 7-15awith aminoethylphosphonate, NaBH₃CN, and AcOH. Compound 7-15b isactivated with BOP reagent, then reacts with aminoethylphosphonate togive compound 7-18. Reductive amination of 7-15c withaminoethylphosphonate, followed by hydrogenation in the presence of 10%Pd/C furnishes desired 7-17. Hydrogenation of 7-15d, followed bytreating with aminoethylphosphonate in the presence of coupling agente.g, BOP reagent. DIC give the desired product 7-16.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 8 Preparation of Exemplary Compounds of the Present Invention

Derivatives of hycamtin at C-10 and O-20 are readily prepared fromhycamtin (topotecan) (U.S. Pat. No. 5,004,758), as illustrated inSchemes 8.1-8.5. Hycamtin is reacted with appropriate triflatedphosphonate to yield analogs of 8-2. Activation of hycamtin withp-nitrophenyl chloroformate, followed by reaction with appropriateaminophosphonate nucleophile furnishes the desired analog 8-4 containinga carbamate linkage.

Conversion of OH group at C-10 to Triflate derivative, followed by COinsertion, and then reaction with aminophosphonate to give analog 8-7.The triflate is converted to an aldehyde by CO insertion, followed byreductive amination with aminophosphonate to give analogs of 8-6.Protection of OH at C-10 and activation of OH-20, followed by reactionwith an aminophosphonate furnishes the desired analogs of 8-8.

Analogs 8-12 are synthesized from Pd-catalyzed reduction of triflated8-10, followed by activation of 0-20 with p-nitrophenyl chloroformate,and reaction with an aminophosphonate. Methylation of hycamtin bytreating hycamtin with NaH, CH₃I in DMF affords 10-OCH₃ hycamtin.Analogs 8-14 are furnished from OCH₃ hycamtin derivative in the samemanner as 8-12.

Preparation of analogs 8-17 is performed by reaction of10-hydroxycamprtothecin with paraformaldehyde, methylamine and aceticacid, followed by reductive amination with an aldehyde-phosphonate.

As depicted in Scheme 8.6, hycamtin is reacted with diethylphosphonatein the presence of Cs₂CO₃ in acetonitrile to afford compound 8-18.Activation of OH-10 by reaction with p-nitrophenyl chloroformate inCH₂Cl₂ in the presence of DIPEA, followed by reaction aminophonatefurnishes carbamate 8-20.

As shown in Scheme 8.7, tirflation of the 10-OH of hycamtin (J. Am.Chem. Soc., 1984, 106, 7500), followed by CO insertion gives thealdehyde intermediate. (J. Org. Chem. 1999, 64, 178). Reductiveamination of aldehyde with aminophosphonate, followed by acid treatment,produces amine 8-21. Triflation and CO insertion of hycamtin gives thecarboxylic acid, (J. Org. Chem. 1994, 59, 6683). The resultingcarboxylic acid is activated with BOP-reagent, followed by reaction withaminophosphonate in the presence of DIPEA to produce compound 8-22.Protection of the 10-OH with TMS—Cl, activation of the 20-OH withp-nitrophenyl chloroformate, followed by reaction with anaminophosphonate furnishes phosphonate 8-23.

Syntheses of 8-24 and 8-25 (see 8-12 and 8-14) are described in Schemes8.8 and 8.9. Dehyroxylation of 8-10 is performed in DMF with dppp,Pd(OAc)₂, and Et₃SiH to yield 8-11. Compound 8-24 is prepared from 8-11by activation with p-nitrophenyl chloroformate, followed by couplingwith aminophosphonate and acid work up.

Hycamtin is treated with NaH in DMF, and reacts with CH₃I to give10-methoxy derivative (Scheme 8.9). This 10-methoxy intermediate isactivated with p-nitrophenyl chloroformate, followed by reaction withaminophosphonate and acid work up to furnish desired phosphonate 8-25.

Scheme 8.10 describes the synthesis of compound 8-26 (an example ofanalogs 8-17), reductive amination of9-methylaminomethyl-10-hydroxycamptothecin 8-16 (prepared as hycamtindescribed in U.S. Pat. No. 5,004,758, using methylamine instead ofdimethylamine) with phosphonate with aldehyde functional group givesdesired product 8-26.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 9 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

Syntheses of examples of analogs 9-2 to 9-8 are illustrated in Schemes9.2, 9.3 and 9.4. Reaction of ketone 9-9 (Chem. Lett. 1980, 51) and1,2,4-triazole with n-BuLi in THF at −78° C. gives alcohol 9-10.Compound 9-10 is reacted with triflated phosphonate and NaH, to yield9-12, an example of 9-7, where X=—CH₂—. Compound 9-10 is activated withp-nitrophenyl chloroformate, followed by reaction withaminoethylphosphonate in the presence of diisopropylethylamine (DIPEA)to furnish the desired produce 9-11, an example of analogs 9-8, whereX=—CH₂CH₂—.

For example, 1,2,4-tetrazole ester derivative is stirred withalpha-bromo-4-tolunirile in CH₂Cl₂ to finish 9-13 (U.S. Pat. No.4,978,672). Compound 9-13 is first saponified with LiOH to generate acid9-14. The acid is reacted with 154-fluorbenzonitrile according toprocedure described in U.S. Pat. No. 4,978,672 to give the keyintermediate 9-15. Reaction of 9-15, DIC, HOAt, andaminoethylphosphonate furnishes 9-16, an example of analogs 9-2, whereX=—CH₂CH₂—. Reduction of 9-15 with borane in THF, followed by reactingwith triflated phosphonate and NaH gives the desired product 9-18, anexample of analogs 9-4, where X=—CH₂CH₂—.

Oxidization of 9-17 with MnO₂ affords aldehyde derivative 9-19.Treatment 9-19 with aminoethylphosphonate generates 9-22, an example ofanalogs 9-5, where X=—CH₂CH₂—. Aldehyde 9-19 is reacted withhydroxyamine, followed by reacting with triflated phosphonate to furnish9-21, an example of analogs 9-6, where X=—CH₂CH₂—. Compound 9-20 isobtained by reductive amination of 9-19 with an aminoethylphosphonate,NaBH₃CN, and AcOH.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 10 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above. Syntheses ofnew compounds containing phosphonate with various linker X areillustrated in Schemes 10.2, 10.3 and 10.4. Examples are synthesized asdepicted in Schemes 10.2, 10.3 and 10.4.

Compound 10-14 is prepared as previous published procedure (J. Med.Chem. 1991, 34, 725) from 10-12 (J. Heterocyclic Chem. 1975, 2, 577) and10-13 (Bioorg. Med. Chem. Lett. 2001, 11, 1257). Compound 10-14 isprotected with benzyl group by reaction with benzyl bromide and Cs₂CO₃,followed by treating with thionyl chloride, then cyclization with KOt-Bu(J. Med. Chem. 1991, 34, 725) to furnish compound 10-15. Hydrogenationto remove benzyl group gives 10-16. Compound 10-16 is stirring withtriflated phosphonate, Cs₂CO₃ in CH₃CN to give the desired product 10-17(an example of analogs 10-8, X=—CH₂—). Compound 10-16 is activated withp-ntirophenyl chlorofromate in the presence of TEA, followed by teactingwith aminoethylphosphonate to yield 10-18 (an example of analogs 10-7,where X=—CH₂CH₂—).

Compound 10-20 is prepared in the same fashion as compound 10-14, from10-12 and 10-19. Compound 10-21 is synthesized according to theprocedure described above for 10-15, followed by hydrogenation in thepresence of 10% Pd/C to furnish the key intermediate 10-22. Reductiveamination of 10-22 with aldehyde phosphonate, NaBH₃CN, and AcOH givesdesired product 10-23 (an example of analogs 10-9, where X=—CH₂CH₂—).Compound 10-22 is reacted with phosphonate chloroformate in the presenceof TEA to give product 10-25 (an example of analogs 10-11, whereX=—CH₂CH₂—). Example of analogs 10-10 (where X=—CH₂—), compound of 10-24is furnished by reaction 10-22 with phosphonate carboxylic acid and DIC.Formylation of fadrozole with n-BuLi, DMF gives intermediate aldehyde10-26 (J. Med. Chem. 2000, 43, 2165). Further oxidation of 10-26 to giveacid, followed by reaction with aminoethylphosphonate, DIC, and HOAtfurnishes the desired product 10-31 (an example of analogs 10-5, whereX=—CH₂CH₂—). Reductive amination of 10-26 with aldehyde phosphonate,NaBH₃CN, and AcOH give desired product 10-27 (an example of analogs10-2, where X=—CH₂CH₂—). Treating 10-26 with aminoethylphosphonate yield10-30 (an example of analogs 10-6, where X=—CH₂CH₂—).

Reduction of 10-26 with NaBH₄ generates alcohol derivative, followed byreaction with triflated phosphonate and NaH to provide product 10-29 (anexample of analogs 10-4, where X=—CH₂—). The condensation betweencompound 10-26 and hydroxyamine in the presence of TEA to give theoxime. The alkylation of the oxime with a triflated phosphonate and NaHfurnishes the desired compound 10-28 (an example of analogs 10-3, whereX=—CH₂—).

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 11 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

Temozolomide, mitozolomide and their derivatives have been synthesizedby several different synthetic routes (Scheme 11.2).5-Aminoimidazole-4-carbozamide is reacted with alkyl isocyanate to givethe 1-(N-alkylcarbamoyl) derivative. This derivative is treated withsodium nitrite to generate 11-10 (J. Org. Chem. 1997, 62, 7288).Alternatively, 5-aminoimidazole-4-carbozamide is treated with sodiumnitrite to generate a diazonium salt, followed by the reaction withalkyl isocyanate to furnish amide 11-10 (U.S. Pat. No. 5,260,291).Hydrolysis conditions can be selected to hydrolyzed amide 11-10 to acid11-13 (J. Med. Chem. 1990, 33, 1393). The acid 11-13 is converted to analdehyde, followed by reductive amination with an aminophosphonate tofurnish analogs 11-31, by the reaction with an aminophosphonate to giveanalog 11-41, and reaction with hydroxylamine, triflate phosphonate togive 11-51. Compound 11-13 is reacted with an aminophosphonate and acoupling agent to give analogs 11-30. Compounds 11-15, 11-17, 11-18, and11-19, which are examples of 11-30, 11-51, 11-41, and 11-31,respectively, can be prepared as illustrated below (Scheme 11.3).

Temozolomide 11-10 is prepared stepwise, from the reaction of5-aminoimidazole-4-carbozamide with methyl isocyanate in acetonitrile,followed by the nitrosoation with sodium nitrite in 50% acetic acid, andcyclization to give 11-10 (J. Org. Chem. 1997, 63, 7288) Temozolomide isconverted to acid 11-14, by the reaction of 11-10 with sodium nitrite inconcentrated sulfuric acid. The acid chloride is obtained by treatingacid 11-14 with thionyl chloride and a catalytic amount of DMF (J. Med.Chem. 1990, 33, 1393). The reaction of the acid chloride with anaminoethyl phosphonate affords 11-15. The acid chloride can be reactedwith a hydroxymethylamine, followed by reduction with DIBAL in THF togive aldehyde 11-16. The aldehyde is further reacted with aminoethylphosphonate, and reductively aminated with an aminoethyl phosphonate,NaBH₃CN, and AcOH to give 11-18, and 11-19, respectively. Aldehyde 11-16can be reacted with hydroxylamine hydrochloride in the presence of TEAfollowed by reaction with a triflated phosphonate and NaH to generate11-17.

Compound 11-21 and 11-23, which are examples of analogs 11-6 and 11-7,are synthesized as illustrated above in Scheme 11.4. Compound 11-10 islithiated with n-BuLi in THF at −78° C., followed by reaction with DMF,to give aldehyde derivative 11-20. The reductive amination of aldehyde11-20 with aminoethylphosphonate, NaBH₃CN, AcOH affords the desiredproduct 11-21 (an example of analog of 11-6, where X=—CH₂CH₂—).Temozolomide 11-10 can also be lithiated with n-BuLi in THF, followed bythe reaction with CO₂ to afford acid derivative 11-22. Acid 11-22 isreacted with an aminoethyl phosphonate in the presence of couplingagents, e.g., DIC, HOAt, to furnish the desired product 11-23 (anexample of analog of 11-7, where X=—CH₂CH₂—). Further manipulations canbe performed on the phosphonate moiety prior to the final deprotection.These types of transformations are more extensively described in thephosphonate interconversion section herein.

Example 12 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

Syntheses of compounds, 12-10, 12-14, 12-16, 12-15, and 12-13,containing phosphonate moieties, which are examples of analogs 12-2(X=—CH₂—), 12-3 (X=—CH₂CH₂—), 12-4 (X=—CH₂CH₂—), 12-5 (X=—CH₂—), and12-6 (X=—CH₂CH₂—), respectively, are illustrated above in Scheme 12-2.Etoposide is obtained as previous described procedure (U.S. Pat. No.3,408,441). Etoposide is reacted with triflated phosphonate with Cs₂CO₃in acetonitrile to afford phosphonate 12-10. Etoposide is activated withp-nitrophenyl chloroformate, followed by reaction with aminoethylphosphonate in the presence of TEA to give 12-13. Triflation of 12-9with PhN(Tt)₂, followed by the CO insertion in the presence of Pd(OAc)₂,pdpp, TEA in DMF-H₂O gives carboxylic acid derivative 12-12. Compound12-12 is reacted with an aminoethyl phosphonate, DIC, and HOAt to afford12-16. Triflation of etoposide, followed CO insertion in the presence ofPd(OAc)₂, pdpp, TEA, and triethyl silane in DMF gives aldehydeintermediate 12-11. Aldehyde 12-11 is reacted with hydroxylaminehydrochloride and diisopropylethyl amine (DIPEA), followed by thereaction with a triflated phosphonate and NaH to furnish phosphonate12-15. The reductive amination of 12-11 with an aminoethyl phosphonate,NaBH₃CN, and AcOH affords the desired compound 12-14.

As depicted in Scheme 12.3, compound 12-18 is prepared by theglycosylation of 12-17 (Bioorg. Med. Chem. Lett. 1994, 4, 2567) withproper propected β-d-glucopyranose, BF₃-Et₂O in dichloroethane at −20°C. (J. Med. Chem. 1989, 32, 1418). Deprotection of 3′-sugar hydroxylgroup using zinc dust in 2:1 THF-AcOH, followed the deprotection of2′-sugar amino group, and benzyl groups of phosphosate by hydrogentionin the presence of 10% Pd/C gives free amine 12-19. The reductiveamination of amine derivative 12-19 with an aminoethyl phosphonate,NaBH₃CN, and AcOH affords phosphonate 12-20, an example of analog 12-8,where X=—CH₂CH₂—.

As in Scheme 12.4, compound 12-21 is prepared by the described procedurein Bioor. Med. Chem. Lett. 2001, 11, 2667 and J. Med. Chem. 1999, 42,4640. Compound 12-22 is furnished by the glycosylation of 12-17 with12-21, BF₃-Et₂O in dichloroethane at −20° C. (J. Med. Chem. 1989, 32,1418). Deprotection of 2′- and 3′-sugar hydroxyl group using zinc dustin 2:1 THF—AcOH, followed the deprotection of the CBZ-group of theterminal amino group and benzyl groups of phosphate by hydrogenation inthe presence of 10% Pd/C gives free amine 12-23. The reductive aminationof amine 12-23 with an animoethyl phosphonate, NaBH₃CN, and AcOH affordsthe desired compound 12-24, an example of analog 12-7, where X=—CH₂CH₂—,and n=1. Further manipulations can be performed on the phosphonatemoiety prior to the final deprotection. These types of transformationsare more extensively described in the phosphonate interconversionsection herein.

Example 13 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above. Analogs13-15, 13-16, and 13-9 are prepared as outlined in Scheme 13.2.

Compound 13-13 is a precursor of analogs 13-15, 13-16, and 13-9.Syntheses of examples are illustrated in Scheme 13.3. Compound 13-13 issynthesized according to procedure described in U.S. Pat. No. Re.36,617, by alkylation of triazole with benzyl bromide 13-12, followed byhydrogenation of the NO₂ group in the presence of 10% Pd/C. Thereductive amination of 13-13 with an aldehyde phosphonate, NaBH₃CN, andAcOH yields 13-40 (an example of 13-9, where X=—CH₂—). A solution of13-13, carboxylic phosphonate, DIC, HOAt is stirred at room temperaturegenerates product 13-42 (an example of 13-8 and 13-16, X=—CH₂—).Activation of the hydroxymethylphosphonate with phosgene, followed byreaction with amine 13-13 in the presence of diisopropylethyl amine inCH₂Cl₂ affords 13-41 (an example of 13-7 and 13-15, where X=—CH2-).

Analogs 13-2 and 13-4 are prepared as outlined in Scheme 13.4. Compound13-18 is prepared as described procedure (U.S. Pat. No. Re. 36,617).Ester 13-18 is saponified to give acid 13-19, which is the key precursorof analogs 13-2 and 13-4.

As depicted in Scheme 13.5, compound 13-18 is first saponified withLiOH, gives 13-19. Compound 13-19 is reacted with aminoethyl phosphonatein the presence of coupling reagent DIC, HOAt to furnish 13-21 (anexample of 13-2, where X=—CH₂—). Acid 13-19 is reduced to alcohol withBH₃-THF, followed by the reaction with triflated phosphonate, NaH in THFat RT to furnish 13-20 (an example of 13-4, where X=—CH₂—).

Compound 13-22 is obtained from the reduction of ester 13-18. Aldehydederivative 13-22 is an important intermediate for analogs 13-5 and13-24. (Scheme 13.6).

As shown in Scheme 13.7, aldehyde 13-22 is reacted withaminoethylphosphonate to afford the desired product 13-25 (an example of13-3 and 13-52, where X=—CH₂CH₂—). Aldehyde 13-22 is reacted withhydroxylamine, followed by the reaction with triflated phosphonate tofurnish 13-50 (an example of analogs 13-6 and 13-24, where X=—CH₂CH₂—).Compound 13-23 is obtained by the reductive amination of 13-22 andaminoethylphosphonate, NaBH₃CN, AcOH.

Bromo derivative 13-27 is prepared by the described procedure foranastrozole (U.S. Pat. No. Re. 36,617). Compound 13-27 is reacted withGrignard reagent R²MgBr, or R²CH═CH₂ in the presence of a Pd catalyst,to give the vinyl derivative, followed by ozonolysis to furnish aldehyde13-28. Aldehyde 13-28 is converted to analogs 13-36 and 13-10 using theprocedures described in Schemes 13.6 and 13.7.

As shown in Scheme 13.9, compound 13-27 is coupled with CH₂═CH₂ in thepresence of Pd(OAc)₂, n-Bu₃P, K₂CO₃ in DMF at 100° C. (Tetrahedron Lett.2002, 43, 3401), followed by ozonolysis to furnish aldehyde 13-28. Thereductive amination of 13-28 with animoethyl phosphonate, NaBH₃CN, AcOHgives desired product 13-32 (an example of analogs 13-10 and 13-36,where X=—CH₂CH₂—) Reduction of the aldehyde using NaBH₄ gives an alcoholderivative. Reaction of the alcohol derivative with NaH and a triflatedphosphonate in THF generates compound 13-31 (an example of analogs 13-11and 13-10, where X=—CH₂—).

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 14 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

Syntheses of new compounds containing phosphonate are illustrated inScheme 14.2. Diethyl 3-nitrocyclobutane-1,1-dicarboxylate (J. Org. Chem.1989, 54, 2869) is readily converted to the 3-amino derivative in 2steps. Compound 14-12 is obtained from the reaction between3-aminocyclobutane-1,1-dicarboxylic acid sodium salt and PtCl₂(NH₃)₂(U.S. Pat. No. 4,625,927). Compound 14-12 is readily converted toanalogs 14-2, 14-3, and 14-5 by reaction with the proper phosphonate inone or two steps.

As outlined in Scheme 14.3, 3-amino-1,1-dicarboxylic acid is obtainedfrom 3-nitro derivative in 2 steps; first saponification with NaOH, thenhydrogenation in the presence of 10% Pd/C. This dicarboxylic acid isfirst converted to its disodium salt, then is reacted with PtCl₂(NH₃)₂according to the previously reported procedure (U.S. Pat. No. 4,657,729)to give carboplatin analog 14-12. The reaction between 14-12 andphosphonate carboxylic acid, HOAt, and DIC gives 14-13 (an example of14-2, where X=—CH₂—). The reductive amination of 14-12 with aldehydephosphonate, NaBH₃CN, and AcOH affords the desired compound 14-14 (anexample of 14-3, where X=—CH₂CH₂—). The hydroxymethyl phosphonate isactivated with triphosgene to form chloroformate derivative, which isreacted with compound 14-12 in the presence of TEA to furnish thedesired product 14-15 (an example of 14-5, where X=—CH₂—).

Diethyl 3-oxocyclobutane-1,1-dicarboxylate (J. Med. Chem. 1990, 33,2905) is saponified with sodium hydroxide, then reacted withhydroxylamine hydrochloride in the presence of TEA to yield the oximeintermediate 14-17. The oxime dicarboxylic acid is treated with sodiumhydroxide (to form the disodium salt), then is reacted with PtCl₂(NH₃)₂according to previous reported procedure (U.S. Pat. No. 4,657,729) togive carboplatin derivative 14-18. Compound 14-18 is readily convertedto analog 14-33. An example of 14-4, phosphonate 14-19 is prepared bytreating 14-12 with NaH and a triflated phosphonate (Scheme 14.4).

In Scheme 14.5, diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (J. Med.Chem. 1990, 33, 2905) is saponified with sodium hydroxide and thedisodium salt of the dicarboxylic acid is reacted with PtCl₂(NH₃)₂according to the previously reported procedure (U.S. Pat. No. 4,657,729)to afford the 3-hydroxy carboplatin analog 14-22. This analog is readilyconverted to 14-6 by the reaction with a triflated phosphonate. Hydroxyl14-22 is converted to analog 14-7 by the activation of the hydroxylgroup, followed by reaction with an aminophosphonate.3-Hydroxycyclobutane-1,1-dicarboxylic acid 14-21 is oxidized to its3-oxo derivative and can be further converted to 14-23 and 14-24.Compound 14-23 is reacted with PtCl₂(NH₃)₂ according to the previouslyreported procedure (U.S. Pat. No. 4,657,729), followed by hydrogenationand the reductive amination to furnish 14-9. Compound 14-24 is convertedto 14-8 in 3 steps, by hydrogenation, carboplatin formation, andreaction with an aminophosphonate.

As depicted in Scheme 14.6, diethyl3-hydroxycyclobutane-1,1-dicarboxylate (J. Med. Chem. 1990, 33, 2905) issaponified with sodium hydroxide. This dicarboxylic acid disodium saltis reacted with PtCl₂(NH₃)₂ according to previous reported procedure(U.S. Pat. No. 4,657,729) gives the 3-hydroxy carboplatin analog 14-22.This analog is readily to convert to 14-25 (an example of 14-6, whereX=—CH₂—) by the reaction with NaH and a triflated phosphonate. Theactivation of the hydroxyl group with p-nitrophenyl chloroformate gives14-26. The activated acid derivative 14-26 is reacted with aminoethylphosphonate in the presence of TEA to afford the desired product 14-27(an example of 14-7, where X=—CH₂CH₂—).3-Oxocyclobutane-1,1-dicarobxylic acid 14-35 is reacted with Ph₃P═CHCHOor PH₃P═CHCOOBn in CH₂Cl₂ to afford 14-33 and 14-24, respectively. Thedisodium salt of compound 14-33 is reacted with PtCl₂(NH₃)₂ to form acarboplatin derivative, followed by hydrogenation in the presence of 10%Pd/C to reduce the double bond, and reductive amination with aminoethylphosphonate, NaBH₃CN, and AcOH affords the desired 14-28 (an example of14-9, where X=—CH₂CH₂—). The disodium salt of compound 14-33 is reactedwith PtCl₂(NH₃)₂ followed by the reductive amination with aminoethylphosphonate, NaBH₃CN, and AcOH to furnish 14-29 (an unsaturated analogof 14-28). Compound 14-30 is synthesized from 14-24 by the hydrogenationin the presence of 10% Pd/C followed by the reaction with PtCl₂(NH₃)₂,and the reaction with aminoethyl phosphonate, DIC, AcOH (an example of14-8, where X=—CH₂CH₂—).

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 15 Preparation of Exemplary Compounds of the Present Invention

Phosphonate analogs 15-2 are readily prepared from 1-alkanoyloxymethylsteroid 15-3 (U.S. Pat. No. 4,591,585), as illustrated in Scheme 15.2.The introduction of methylene group at position 6 can be accomplishedaccording to the method reported in literature (Synthesis 1982, 34).Hydrolysis of 15-4 affords the 1-hydroxymethyl steroid 15-5. Alkylationof 15-5 with the phosphonate reagent affords desired compounds 15-2.

Scheme 15.3 shows an example for the preparation of a phosphonate analogof exemestane. 1-Acetyloxymethyl steroid 15-6 is treated withformaldehyde acetal, phosphorus oxychloride and sodium acetate inchloroform to give 6-methylene compound 15-7. Hydrolysis of 15-7 withsodium hydroxide give 1-hydroxymethyl steroid 15-5. Alkylation of 15-5with phosphonate triflate afford desired product 15-8.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 16 Preparation of Exemplary Compounds of the Present Invention

Phosphonate analogs 16-2 are readily prepared from 1-acetyloxymethylsteroid 16-3 (U.S. Pat. No. 4,591,585), as illustrated in Scheme 16.2.Hydrolysis of 16-3 give 1-hydroxymethyl steroid 16-4. Alkylation of 16-4with the phosphonate reagent affords desired compounds 16-2.

Scheme 16.3 shows an example for preparation of phosphonate analog ofatamestane. 1-Acetyloxymethyl steroid 16-3 is hydrolized with sodiumhydroxide to give 1-hydroxymethyl steroid 16-4. Alkylation of 16-4 witha phosphonate triflate afford desired product 16-5.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 17 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

As illustrated in Scheme 17.2, phosphonate analogs of type 17-2 arereadily prepared from epirubicin (17-1) via reductive alkylation of theamine with phosphonate aldehydes.

For example (Scheme 17.3), reductive alkylation of epirubicin 17-1 withaldehyde 17-15 (Synth. Commun. 1992, 22, 2219) give desired compound17-5.

As illustrated in Scheme 17.4, phosphonate analogs of type 17-3 arereadily prepared from protected epirubicin 17-6 (accessible by themethods reported in J. Org. Chem. 1997, 42, 3653) via alkylation withappropriate phosphonate reagent.

For example (Scheme 17.5), alkylation of tri-protected epirubicin 17-7with phosphonate triflate, followed by basic (0.1N sodium hydroxide) andacidic (80% acetic acid) deprotection, afford compound 17-8.

As illustrated in Scheme 17.6, phosphonate analogs of type 17-4 arereadily prepared from epirubicin intermediate 17-9 (accessible by themethods reported in J. Med. Chem. 1985, 28, 1223) via a displacement ofthe leaving group X with appropriate nucleophiles.

For example (Scheme 17.7), reaction of bromide 17-11 with phosphonateamine, followed by a deprotection, affords desired product 17-12.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in phosphonate interconversion section herein.

Example 18 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above.

As illustrated in Scheme 18.2, phosphonate analogs of type 18-2 arereadily prepared from adriamycin 18-1 via reductive alkylation of theamine with phosphonate aldehydes.

For example (Scheme 18.3), reductive alkylation of adriamycin 18-1 withaldehyde 18-15 (Synth. Commun. 1992, 22, 2219) give desired compound18-5.

As illustrated in Scheme 18.4, phosphonate analogs of type 18-3 arereadily prepared from protected adriamycin 18-6 (J. Org. Chem. 1997, 42,3653) via alkylation with appropriate phosphonate reagent.

For example (Scheme 18.5), alkylation of tri-protected adriamycin 18-7with phosphonate triflate, followed by basic (0.1N sodium hydroxide) andacidic (80% acetic acid) deprotection, afford compound 18-8.

As illustrated in Scheme 18.6, phosphonate analogs of type 18-4 arereadily prepared from adriamycin intermediate 18-9 (J. Med. Chem. 1985,28, 1223) via a displacement of the leaving group X with appropriatenucleophiles.

For example (Scheme 18.7), reaction of bromide 18-10 with phosphonateamine, followed by a deprotection, affords desired product 18-11.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in phosphonate interconversion section herein.

Example 19 Preparation of Exemplary Compounds of the Present Invention

Exemplary compounds of the invention are illustrated above. Analogs oftype 19-2, 19-3 and 19-4 are readily prepared from taxotere 19-1.

Direct alkylation of 19-1 with the phosphonate reagents give analogs oftype 19-2 as major products (Tetrahedron 1993, 49, 2805). Selectiveprotection of taxotere position at C-2′ (J. Org. Chem. 1995, 60, 761)give 19-6, which are then alkylated with the phosphonate reagents,followed by deprotection, to afford analogs of type 19-3 and 19-4.

For example (Scheme 19.3), treatment of taxotere 19-1 withtert-butyldimethylsilyl chloride and triethylamine in DMF give mono-TBSprotected taxotere 19-7. Alkylation of 19-7 with phosphonate triflate,followed by deprotection with tetrabutylammonium fluoride, afforddesired product 19-9 and 19-8. Direct alkylation of taxotere 19-1 withphosphonate triflate can afford analogs of type 19-2.

As illustrated in Scheme 19.4, analogs of type 19-5 can be obtained fromtaxotere analogs 19-12, which are accessible from β-lactam 19-10 andbaccatin III (19-11) according to the methods reported in literature(Bioorg. Med. Chem. Lett. 1994, 4, 479; Synlett 1992, 761).

For example (Scheme 19.5), using 4-nitrobenzaldehyde (in place ofbenzaldehyde) as starting material, β-Lactam 19-14 is prepared byliterature procedure (Synlett 1992, 761). Reaction of 19-14 withbaccatin III 19-15 in the presence of 4-dimethylaminopyridine affordscompound 19-16. Reduction of 19-16 with zinc in acetic acid affordsamino compound 19-18. Alkylation of 19-18 with a phosphonate triflatereagent produces desired compound 19-17.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the phosphonate interconversion section herein.

Example 20 Preparation of Exemplary Compounds of the Present Invention

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the following section.

As illustrated in Scheme 20.2, phosphonate analogs of type 20-2, 20-3and 20-4 are readily prepared from taxol 20-1. Direct alkylation of 20-1with the phosphonate reagents gives analogs of type 20-2 as majorproducts (Tetrahedron, (1993), 49, 2805). Selective protection of taxolat C-2′ position (J. Org. Chem. (1995), 60, 761) give 7, which are thenalkylated with the phosphonate reagents, followed by deprotection, toafford analogs of type 20-3. Full protection of taxol at position C-2′and C-7 give 20-8, then the C-10 hydroxyl of 20-8 is revealed andalkylated with the phosphonate reagents, followed by deprotection, tofurnish analogs of type 20-4. For example (Scheme 20.3), treatment oftaxol 20-1 with excess of tert-butyldimethylsilyl chloride andtriethylamine in DMF gives bis-TBS protected taxol 8a. Treatment of 8awith hydrazine in ethanol gives compound 20-11 (J. Org. Chem. (1995),60, 761). Alkylation of 20-11 with phosphonate triflate, followed bydeprotection with tetrabutylammonium fluoride, afford desired product20-10.

As illustrated in Scheme 20.4, analogs of type 20-5 can be obtained fromtaxol analogs 20-14, which are accessible from β-lactam 20-12 andbaccatin III (20-13, 20-16) according to the methods reported inliterature (Bioorg. Med. Chem. Lett. (1994), 4, 479; Synlett. (1992),761). For example (Scheme 20.5), using 4-nitrobenzoyl chloride (insteadof benzoyl chloride) as starting material, β-Lactam 20-15 is prepared byliterature procedure (Synlett. (1992), 761). Reaction of 20-15 withbaccatin III in the presence of 4-dimethylaminopyridine give compound20-17. Reduction of 20-17 with zinc in acetic acid affords aminocompound 20-19. Alkylation of 20-19 with phosphonate triflate reagentproduces desired compound 20-18.

As shown in Scheme 20.6 and Scheme 20.7, analogs of type 20-6 can beprepared in the same fashion as type 20-5.

Example 21 Preparation of Exemplary Compounds of the Present Invention

Further manipulations are performed on the phosphonate moiety prior tothe final deprotection. These types of transformations are moreextensively described in the following section.

As illustrated in Scheme 21.2, the strategy for the synthesis ofphosphonate analogs of type 21-2 is first to introduce the phosphonatemoiety into catharanthine 21-5 to give 21-7, which then is connected tovindoline 21-10 and converted into final compounds 21-2 using the samemethods used in the synthesis of vinorelbine (Bioorg. Med. Chem. Lett.(2002), 12, 505; Tetrahedron (1980), 36, 3053).

For example (Scheme 21.3), catharanthine 21-5 is hydrolyzed with sodiumhydroxide to give 21-6. Coupling of 21-6 with phosphonate amine affords21-9. The conversion of 21-9 and vindoline 21-10 into compound 21-11 isaccomplished by sequential treatments of 3-chloroperoxybenzoic acid(mCPBA), trifluoroacetic anhydride (TFAA) and sodium borohydride.Treatment of 21-11 with N-bromosuccinimide (NBS), followed by silvertetrafluoroborate, affords desired compound 21-12.

As illustrated in Scheme 21.4, a similar strategy is used in thesynthesis of phosphonate analogs of type 21-3. The phosphonate moiety isfirst introduce into vindoline 21-10 to give 21-14, which then isconnected to catharanthine 21-5 and converted into final compounds 21-3using the same methods used in the synthesis of vinorelbine.

For example (Scheme 21.5), hydrolysis of vindoline 21-10 with sodiumhydroxide, followed by reprotection of the hydroxyl, gives 21-20.Coupling of 21-20 with phosphonate amine affords 21-15. Finally, 21-15and 21-5 are converted to desired product 21-17 in the same manner asdescribed above.

As illustrated in Scheme 21.6, phosphonate analogs of type 21-4 arereadily prepared from vinorelbine 21-1. Hydrolysis of 21-1 gives 21-18,which is then alkylated with phosphonate reagents to afford analogs oftype 21-4.

For example (Scheme 21.7), treatment of 21-1 with sodium methoxide inanhydrous methanol results in compound 21-18. Alkylation of 21-18 withphosphonate triflate in the presence of sodium hydride affords desiredcompound 21-19.

Example 22 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 22.2-22.3, with examples depicted in Schemes22.4-22.6.

The glucose derived starting material is synthesized from glucose andbenzyl glyoxylate (J. Org. Chem., (2002), 67, 5408-5411) according tothe methods described in Chem. Lett., (1987), 799-802. The glycosidationreaction is performed with 4′chloroacetyl protected epipodophyllotoxin(described in the reference above) under catalysis of boron trifluoride(described in the reference above). The product of this reaction isdissolved in an organic solvent such as ethyl acetate and ishydrogenated in the presence of Pd/C under an atmosphere of hydrogen.The crude reaction mixture is filtered through Celite and the solvent isremoved in vacuo. The crude reaction product is dissolved in an organicsolvent such as DMF or chloroform and is then treated at a temperatureof ˜−10° C. with a tertiary amine base such as diisopropylethylamine(DIEA) and isobutyl chloroformate. After the activation is complete,2-aminoethylphosphonic acid diethyl ester is added. After all startingmaterial is consumed the reaction mixture is washed with aqueous 0.1 MHCl and aqueous bicarbonate solution. After drying and removal of thesolvent the crude product of the coupling is obtained. Furtherpurification is achieved by chromatography. The material is dissolved inan organic solvent such as methanol and is treated with zinc acetate atreflux temperature. At the end of the reaction, the mixture is cooled toroom temperature and the solvent is removed in vacuo. The crude reactionproduct is dissolved in an organic solvent such as chloroform and thesolution is washed with aqueous 0.1 M HCl and aqueous bicarbonatesolution. After drying and removal of the solvent the crude finalproduct is obtained. Further purification is achieved by chromatography.

The starting material (synthesis according to Chem. Lett., (1987),799-804) is treated in an organic solvent such as DCM or THF withdiethyl phosphonato ethyl carbaldehyde and sodium triacetoxyborohydrideas described in J. Org. Chem., (1996), 61, 3849-3862. The reaction isquenched with aqueous sodium bicarbonate and the product is extractedwith an organic solvent such as ethyl acetate. Further purification isachieved by chromatography.

The amine containing starting material (obtained as described in J. Med.Chem., (1991), 34, 3346-3350.) is treated in an organic solvent such asDCM or THF with diethylphosphonato-ethylcarbaldehyde and sodiumtriacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.Further purification is achieved by chromatography.

All final products are converted to the corresponding 4′ phosphateanalogs via treatment of these compounds with phosphoryl trichloride inan organic solvent such as MeCN in the presence of an tertiary organicamine base such as DIEA, followed by treatment with aqueous bicarbonatesolution as described in Bioorg. Med. Chem. Lett., (1994), 21,2567-2572. Final purification is achieved by chromatography.

Example 23 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these are made according to the general route outlinedin Schemes 23.1-23.6, with examples depicted in Schemes 23.7-23.12.

2-Diethyl phosphonatoacetic acid dissolved in an organic solvent such asbenzene, tetrahydrofuran (THF), or chloroform, is combined with atertiary amine base such as diisopropylethylamine (DIEA) and diphenylphosphorazidate (1.2 equiv) and is stirred at room temperature accordingto J. Med. Chem., (1991), 34, 1001-1018. After the acyl azide has beenformed, 4-deacetylvinblastine (prepared from vinblastine according to J.Med. Chem., (2002), 45, 4706-4715) is added, and the reaction mixture isheated to ˜80° C. for ˜4 hrs (Biochemistry (2002), 41, 14010-14018). Thereaction mixture is cooled to room temperature and is washed withaqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonate solutionand dried. Removal of the solvents yields the crude product. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such asacetonitrile and the solution is cooled to −20° C. A strong inorganicacid such as perchloric acid (2 equiv) is added, followed by ferrousperchlorate and hydrogen peroxide (excess), according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990). At the end ofthe reaction aqueous ammonium hydroxide is added and the reactionmixture is extracted with an organic solvent such as dichloromethane(DCM). Removal of solvents in vacuo yields the crude product. Furtherpurification is achieved by chromatography.

The starting material (synthesis published in J. Med. Chem., (1978), 21,88-96; from vinblastine) is treated in an organic solvent such as DCM orTHF with 2-aminoethylphosphonic acid diethyl ester at room temperature,according to the procedure described in J. Med. Chem., (1979), 22,391-400. At the end of the reaction, the solution is washed with water,aqueous bicarbonate and water, and is dried. Evaporation of solventsyields the crude product. Further purification is achieved bychromatography.

The product of this step is dissolved in an organic solvent such as DCMor THF. Pyridine is added, followed by acetic anhydride, and thereaction is stirred at room temperature according to J. Med. Chem.,(1979), 22, 391-400. At the end of the reaction, methanol is added andthe solvents are removed in vacuo. The crude material is dissolved in anorganic solvent such as DCM, washed with water and aqueous bicarbonatesolution and dried. Removal of the solvents in vacuo yields the crudeproduct. Further purification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such asacetonitrile and the solution is cooled to −20° C. A strong inorganicacid such as perchloric acid (2 equiv) is added, followed by ferrousperchlorate and excess hydrogen peroxide, according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990). At the end ofthe reaction aqueous ammonium hydroxide is added and the reactionmixture is extracted with an organic solvent such as DCM. Removal ofsolvents in vacuo yields the crude product. Further purification isachieved by chromatography.

2-Diethyl phosphonatoacetic acid is dissolved in an organic solvent suchas benzene, THF, or chloroform, and is combined with a tertiary aminebase such as diisopropylethylamine (DIEA) and diphenyl phosphorazidate(1.2 equiv) and is stirred at room temperature, according to J. Med.Chem., (1991), 34, 1001-1018. After the acyl azide has been formed,N-1-(β-hydroxyethylthiomethyl)vinblastine (prepared according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990), fromvinblastine via CrO₃-mediated oxidation in the presence of methanol andsubsequent methoxy displacement with β-hydroxy thioethanol) is added,and the reaction mixture is heated to ˜80° C. for ˜4 hrs (Biochemistry(2002), 41, 14010-14018). The reaction mixture is cooled to roomtemperature, washed with aqueous HCl (1N) and aqueous bicarbonatesolution, and dried. Removal of the solvents yields the crude product.Further purification is achieved by chromatography.

Vinblastine and diethyl (cyanomethyl)phosphonate (commerciallyavailable) are dissolved in conc. sulfuric acid at a temperature of ˜0°C., according to a procedure from Pearce, “Medicinal Chemistry ofBisindole Alkaloids from Catharanthus”, in The Alkaloids, Vol. 37, 145,Academic Press San Diego, (1990) (described for acetonitrile). When thestarting material is consumed the reaction mixture is carefully dilutedwith water and further neutralized. The crude reaction mixture isextracted with an organic solvent such as DCM. The combined organicextracts are washed aqueous bicarbonate solution and dried. Removal ofthe solvents yields the crude product. Further purification is achievedby chromatography.

The product of this step is dissolved in an organic solvent such asacetonitrile and the solution is cooled to −20° C. A strong inorganicacid such as perchloric acid (2 equiv) is added, followed by ferrousperchlorate and excess hydrogen peroxide, according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990). At the end ofthe reaction aqueous ammonium hydroxide is added and the reactionmixture is extracted with an organic solvent such as DCM. Removal ofsolvents in vacuo yields the crude product. Further purification isachieved by chromatography.

C12′-Iodo-vinblastine (prepared according to Pearce, “MedicinalChemistry of Bisindole Alkaloids from Catharanthus”, in The Alkaloids,Vol. 37, 145, Academic Press San Diego, (1990), by iodination ofvinblastine with ferrous perchlorate, tetra(n-propyl)ammoniumperiodinate and a catalytic amount of ruthenium dioxide) is added to amixture of copper(I) iodide and potassium phosphate and2-aminoethylphosphonic acid diethyl ester (commercially available). Thereaction mixture is heated under an inert gas atmosphere to ˜80° C.,according to a procedure from Buchwald in Org. Lett., (2002), 4,581-584. At the end of the reaction the material is cooled to roomtemperature and the solvent is removed in vacuo. The crude reactionmixture is extracted with an organic solvent such as DCM. The combinedorganic extracts are washed with aqueous bicarbonate solution and dried.Removal of the solvents yields the crude product. Further purificationis achieved by chromatography. The product of this step is dissolved inan organic solvent such as DCM or THF. Pyridine is added, followed byacetic anhydride, and the reaction is stirred at room temperatureaccording to J. Med. Chem., (1979), 22, 391-400. At the end of thereaction, methanol is added and the solvents are removed in vacuo. Thecrude material is dissolved in an organic solvent such as DCM and iswashed with water and aqueous bicarbonate solution and is dried. Removalof the solvents in vacuo yields the crude product. Further purificationis achieved by chromatography.

The product of this step is dissolved in an organic solvent such asacetonitrile and the solution is cooled to −20° C. A strong inorganicacid such as perchloric acid (3 equiv) is added, followed by ferrousperchlorate and excess hydrogen peroxide, according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990). At the end ofthe reaction aqueous ammonium hydroxide is added and the reactionmixture is extracted with an organic solvent such as DCM. Removal ofsolvents in vacuo yields the crude product. Further purification isachieved by chromatography.

The starting material (prepared according to Pearce, “MedicinalChemistry of Bisindole Alkaloids from Catharanthus”, in The Alkaloids,Vol. 37, 145, Academic Press San Diego, (1990), by exhaustive hydrolysisof vinblastine in NaOH (5N) under refluxing conditions) is dissolved inan organic solvent such as dimethylformamide (DMF) at room temperature.Methyl iodide (1 equiv) is added, followed by potassium carbonate.Stirring at room temperature is continued. At the end of the reaction,the reaction is filtered and the solvent is removed in vacuo. Thedesired C24 methyl ester is purified by chromatography. The product ofstep 1 is dissolved in an organic solvent such as DCM or DMF and thesolution is cooled to −10° C. A tertiary amine base such as DIEA isadded, followed by a coupling reagent such as iso-butylchloroformate.Stirring at −10° C. is continued until the activation is complete.Aminoethylphosphonic acid diethyl ester is added and stirring with slowwarming to 0° C. is continued. At the end of the reaction, the solutionis warmed to room temperature and the solvent is removed in vacuo. Theproduct is further purified by chromatography. The product of this stepis dissolved in an organic solvent such as DCM or THF. Pyridine isadded, followed by acetic anhydride, and the reaction is stirred at roomtemperature according to J. Med. Chem., (1979), 22, 391-400. At the endof the reaction, methanol is added and the solvents are removed invacuo. The crude material is dissolved in an organic solvent such asDCM, washed with water and aqueous bicarbonate solution, and dried.Removal of the solvents in vacuo yields the crude product. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such asacetonitrile and the solution is cooled to −20° C. A strong inorganicacid such as perchloric acid (2 equiv) is added, followed by ferrousperchlorate and excess hydrogen peroxide, according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990). At the end ofthe reaction aqueous ammonium hydroxide is added and the reactionmixture is extracted with an organic solvent such as DCM. Removal ofsolvents in vacuo yields the crude product. Further purification isachieved by chromatography.

Example 24 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared according to the generalroute outlined in Schemes 24.1 and 24.3, with examples depicted inSchemes 24.2 and 24.4.

The 2-chloro-2′-deoxyadenosine 24-1 (prepared according to the procedureof Ikehara, M. et al., J. Am. Chem. Soc., (1963), 85, 2344, also seeIkehara, M. et al., J. Am. Chem. Soc., (1965), 87, 3, 606) can betreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester24-2, 24-3.

The preparation of compound 24-7, 24-13 is described in Scheme 24.3.Compound 24-1 (2-chloro-2′-deoxyadenosine) can be prepared as describedin Ikehara, M. et al., J. Am. Chem. Soc., (1963), 85, 2344; see alsoIkehara, M. et al., J. Am. Chem. Soc., (1965), 87, 3, 606. Oxidation ofthe 5′-OH followed by elimination provides glycal 24-4 (see theprocedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9,3213). Protection of the chloroadenine at the 6 position followed byselenoetherification provides the protected phosphonate 24-5, 24-10(Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative eliminationof the phenylselenide (as described in Kim, C. et al., J. Org. Chem.,(1991), 56, 2642) followed by stereoselective dihydroxylation providesthe diol which can then be converted to the 3′ monoprotected sugar.Acylation of the 2′ alcohol with phenyl chlorothionoformate provides theprecursor for Robins deoxygenation. Subsequent deoxygenation providescompound 24-6, 24-12 (Metteucci, M. D. et al., Tetrahedron Lett.,(1987), 28, 22, 2469, see also Robins, M. J. et al., J. Org. Chem.,(1995), 60, 7902). Finally, the protecting groups are removed.

Specifically, 2-chloro-2′-deoxyadenosine, compound 24-1 can be oxidizedwith PtO₂ to provide carboxylic acid 24-8. Decarboxylative eliminationis achieved using dimethylformamide dineopentyl acetal in DMF at hightemperature (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9,3213). Once the furanoid glycal 24-4 is in hand, it is first protectedat the 6-position of the 2-chloroadenosine using PivCl conditions asdescribed in Greene, T., Protective groups in organic synthesis,Wiley-Interscience, 1999. Treatment of the protected glycal with silverperchlorate in the presence of diethyl(hydroxymethyl)phosphonate(Phillion, D. et al., Tetrahedron Lett., 1986, 27, 1477) provides thephosphonate 24-5, 24-10 (Kim, C. et al., J. Org. Chem., (1991), 56,2642). Oxidative elimination of the selenide followed by dihydroxylationusing osmium tetraoxide provides a diol which can be monoprotected atthe 3′ position using a THP group. Further acylation of the 2′ alcoholwith phenyl chlorothionoformate provides the precursor for Robinsdeoxygenation, performed with tributyltin hydride, to give compound24-6, 24-12 (Metteucci, M. D. et al., Tetrahedron Lett., (1987), 28, 22,2469, also see Robins, M. J. et al., J. Org. Chem., (1995), 60, 7902).Deprotection of the pivaloyl group by treatment with sodium methoxide(Greene, T., Protective groups in organic synthesis, Wiley-Interscience,(1999)) is followed by a final deprotection of the THP group in aceticacid.

Example 25 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 25.1-25.5, with specific examples depicted inSchemes 25.2-25.5. Final compounds, be they diastereoisomers orenantiomers, may be purified by chromatographic means.

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventlike diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added. After consumption of the activated speciesis observed the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604.).When the activation is complete,(L)-2-amino-6-(diethylphosphonato)-hexanoic acid is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the product is isolated via chromatography. Alternatively,the product can be isolated through precipitation from the reactionsolution with an organic solvent like diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 4-amino-4-(diethylphosphonato)-butyric acidtert butylester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added.After consumption of the activated species is observed the solvent isremoved in vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith trifluoroacetic acid (TFA). The product is isolated viachromatography after removal of the solvents. Alternatively, the productcan be isolated through precipitation form the reaction solution with anorganic solvent like diethyl ether or the like.

Example 26 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 26.1-26.5, with specific examples depicted inSchemes 2-4. Final compounds, be they diastereoisomers or enantiomers,may be purified by chromatographic means.

In case a direct coupling to aminopterin is hampered by the presence ofa free secondary amine in the starting material (R=H), this entity istemporarily protected either with a tert-butoxycarbonyl group (R=Boc) orbenzyloxycarbonyl (R=Cbz or Z) according to standard procedures (GreenWutts: Protective groups in organic chemistry)

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed by filtration and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added. After consumption of the activated speciesis observed the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed by filtration and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604.).When the activation is complete,(L)-2-amino-6-(diethylphosphonato)-hexanoic acid is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the product is isolated via chromatography. Alternatively,the product can be isolated through precipitation from the reactionsolution with an organic solvent such as diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed by filtration and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 4-amino-4-(diethylphosphonato)-butyric acidtert butylester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added.After consumption of the activated species is observed the solvent isremoved in vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventsuch as diethyl ether or the like.

In case R=Z: The compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

Example 27 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routesoutlined in Schemes 27.1 and 27.3, with exemplifications in Scheme 27.2and Schemes 27.4-27.6.

The bis-anisole derivative of flavopiridol (see Bioorg. Med. Chem.Lett., (2000), 10, 1037) serves as an ideal starting point forattachment of a phosphonate moiety to the piperidine nitrogen. Followingprotection of the alcohol, the tertiary amine is demethylated andderivatized with the reagent of choice. Removal of the methyl ethers andthe protecting group on the alcohol gives the desired analogs.

An example of an alvocidib analog with a phosphonate moiety linked tothe piperidine nitrogen in this manner is illustrated in Scheme 27.2.

The alcohol is protected as the acetate under standard conditions (seeGreene, T., Protective groups in organic synthesis, Wiley-Interscience,(1999)). Demethylation of the N-methylpiperidine is achieved throughreaction with α-chloroethyl chloroformate in the presence of a base suchas N,N-diisopropylethylamine (DIEA) followed by brief heating in acidicmethanol. The liberated secondary amine is condensed with(2-oxo-ethyl)-phosphonic acid diethyl ester under reductive conditionssuch as those achieved through the use of sodium cyanoborohydride in asolvent such as methanol or dimethylformamide (see Tet. Lett. (1990),31, 5595). The alcohol is de-acetylated by treatment with sodiumethoxide in ethanol. Finally, bis-demethylation is achieved by heatingwith pyridinium hydrochloride (see Bioorg. Med. Chem. Lett., (2000), 10,1037).

The 2-hydroxyacetophenone (see Bioorg. Med. Chem. Lett., (2000), 10,1037) is treated with a suitable phosphonate-bearing benzoyl chloridederivative. The flavone ring system is formed by cyclization, and themethyl groups are removed.

Such a synthesis is exemplified in Scheme 27.4.

Condensation with [4-(2-chlorocarbonyl-phenoxy)-but-2-enyl]-phosphonicacid diethyl ester (synthesis below) is followed by successive treatmentwith sodium hydride, hydrochloric acid and sodium carbonate, generatingthe 5,7-dimethoxyflavone. Demethylation to provide the5,7-dihydroxyflavone final product is achieved as in Scheme 27.2 (seeBioorg. Med. Chem. Lett., (2000), 10, 1037).

Salicylic acid methyl ester is treated in a solvent such asdimethylformamide or tetrahydrofuran with a base such as sodium hydride.When bubbling ceases, E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. The resultingmonobromide is heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the diethylester of the desired phosphonic acid. The methyl ester is saponifiedwith lithium hydroxide and the acid chloride generated by treatment withoxalyl chloride in a solvent such as dichloromethane in the presence ofa catalytic amount of dimethylformamide.

A synthesis of another suitable acid chloride is exemplified below.

The phenol is treated in a solvent such as tetrahydrofuran ordimethylformamide with a base such as sodium hydride. When bubblingceases, diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477) is added, yielding the desiredphosphonate diester.

Similarly, a reagent suitable for generating an analog with aphosphonate moiety attached to the 4-position of the phenyl ring at theflavone 2-position may be generated from 4-hydroxybenzoic acid methylester.

Example 28 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of vinblastine which, upon cleavage insidethe target cell, give rise to an agent with an increased intracellularhalf-life. Such compounds are described below.

Compounds such as these can be made according to the general routeoutlined in Schemes 28.2-28.7, with examples depicted in Schemes28.8-28.13.

2-Diethyl phosphonatoacetic acid is dissolved in an organic solvent suchas benzene, tetrahydrofuran (THF), or chloroform, and is combined with atertiary amine base such as diisopropylethylamine (DIEA) and diphenylphosphorazidate (1.2 equiv) and is stirred at room temperature,according to J. Med. Chem., (1991), 34, 1001-1018. After the acyl azidehas been formed, 4-deacetyl vinblastine (prepared according to J. Med.Chem., (2002), 45, 4706-4715 from vinblastine) is added and the reactionmixture is heated to ˜80° C. for ˜4 hours (Biochemistry, (2002), 41,14010-14018). The reaction mixture is cooled to room temperature and iswashed with aqueous hydrochloric acid (HCl) (1N) and aqueous bicarbonatesolution and dried. Removal of the solvents yields the crude product.Further purification is achieved by chromatography.

The starting material (synthesis published in J Med. Chem., (1978), 21,88-96; from vinblastine) is treated in an organic solvent such asdichloromethane (DCM) or THF with 2-aminoethylphosphonic acid diethylester at room temperature, according to the procedure described in J.Med. Chem., (1979), 22, 391-400. At the end of the reaction, thesolution is washed with water, aqueous bicarbonate and water, and isdried. Evaporation of solvents yields the crude product. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such as DCMor THF. Pyridine is added followed by acetic anhydride and the reactionis stirred at room temperature, according to J. Med. Chem., (1979), 22,391-400. At the end of the reaction, methanol is added and the solventsare removed in vacuo. The crude material is dissolved in an organicsolvent such as DCM and is washed with water and aqueous bicarbonatesolution and is dried. Removal of the solvents in vacuo yields the crudeproduct. Further purification is achieved by chromatography.

2-Diethyl phosphonatoacetic acid is dissolved in an organic solvent suchas benzene, THF, or chloroform, and is combined with a tertiary aminebase such as diisopropylethylamine (DIEA) and diphenyl phosphorazidate(1.2 equiv) and stirred at room temperature, according to J. Med. Chem.,(1991), 34, 1001-1018. After the acyl azide has been formed,N-1-(β-hydroxyethylthiomethyl)vinblastine (prepared according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids Vol. 37, 145, Academic Press San Diego, (1990), fromvinblastine, via CrO₃-mediated oxidation in the presence of methanol andconsecutive methoxy displacement with β-hydroxy thioethanol) is added,and the reaction mixture is heated to ˜80° C. for ˜4 hrs (Biochemistry(2002), 41, 14010-14018). The reaction mixture is cooled to roomtemperature and is washed with aqueous HCl (1N) and aqueous bicarbonatesolution and dried. Removal of the solvents yields the crude product.Further purification is achieved by chromatography.

Vinblastine and diethyl cyanomethylphosphonate (commercially available)are dissolved in conc. sulfuric acid at a temperature of ˜0° C.,according to a procedure from Pearce, “Medicinal Chemistry of BisindoleAlkaloids from Catharanthus” in The Alkaloids Vol. 37, 145, AcademicPress San Diego, (1990). When the starting material is consumed, thereaction mixture is carefully diluted with water and furtherneutralized. The crude reaction mixture is extracted with an organicsolvent such as DCM. The combined organic extracts are washed withaqueous bicarbonate solution and dried. Removal of the solvents yieldsthe crude product. Further purification is achieved by chromatography.

C12′-Iodo-vinblastine (prepared according to Pearce, “MedicinalChemistry of Bisindole Alkaloids from Catharanthus”, in The AlkaloidsVol. 37, 145, Academic Press San Diego, (1990), by iodination ofvinblastine with ferrous perchlorate, tetra(n-propyl)ammoniumperiodinate and a catalytic amount of ruthenium dioxide) is added to amixture of copper(I) iodide and potassium phosphate and2-aminoethylphosphonic acid diethyl ester (commercially available). Thereaction mixture is heated under an inert gas atmosphere to ˜80° C.,according to a procedure from Buchwald in Org. Lett., (2002), 4,581-584. At the end of the reaction the material is cooled to roomtemperature and the solvent is removed in vacuo. The crude reactionmixture is extracted with an organic solvent such as DCM. The combinedorganic extracts are washed with aqueous bicarbonate solution and dried.Removal of the solvents yields the crude product. Further purificationis achieved by chromatography. The product of this step is dissolved inan organic solvent such as DCM or THF. Pyridine is added, followed byacetic anhydride, and the reaction is stirred at room temperatureaccording to J. Med. Chem., (1979), 22, 391-400. At the end of thereaction, methanol is added and the solvents are removed in vacuo. Thecrude material is dissolved in an organic solvent such as DCM and washedwith water and aqueous bicarbonate solution and dried. Removal of thesolvents in vacuo yields the crude product. Further purification isachieved by chromatography.

The starting material (prepared according to Pearce, “MedicinalChemistry of Bisindole Alkaloids from Catharanthus”, in The AlkaloidsVol. 37, 145, Academic Press San Diego, (1990), by exhaustive hydrolysisof vinblastine in NaOH (5N) under refluxing conditions) is dissolved inan organic solvent such as dimethylformamide (DMF) at room temperature.Methyl iodide (1 equiv) is added, followed by potassium carbonate.Stirring at room temperature is continued. At the end of the reaction,the reaction is filtered and the solvent is removed in vacuo. Thedesired C24 methyl ester is purified by chromatography. The product ofstep 1 is dissolved in an organic solvent such as DCM or DMF and thesolution is cooled to −10° C. A tertiary amine base such as DIEA isadded, followed by a coupling reagent such as iso-butylchloroformate.Stirring at −10° C. is continued until the activation is complete.Aminoethylphosphonic acid diethyl ester is added and stirring with slowwarming to 0° C. is continued. At the end of the reaction, the solutionis warmed to room temperature and the solvent is removed in vacuo. Theproduct is further purified by chromatography. The product of this stepis dissolved in an organic solvent such as DCM or THF. Pyridine isadded, followed by acetic anhydride, and the reaction is stirred at roomtemperature according to J. Med. Chem., (1979), 22, 391-400. At the endof the reaction, methanol is added and the solvents are removed invacuo. The crude material is dissolved in an organic solvent such as DCMand washed with water and aqueous bicarbonate solution and dried.Removal of the solvents in vacuo yields the crude product. Furtherpurification is achieved by chromatography.

Example 29 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of tipifarnib which, upon cleavage insidethe target cell, give rise to an agent with an increased intracellularhalf-life. Such compounds are described below.

Compounds such as these can be made according to the general routesoutlined in Schemes 29.2, 29.4, 29.6, 29.8 and 29.10, with specificexemplifications illustrated in Schemes 29.3, 29.5, 29.7, 29.9 and29.11.

The quinolone (see U.S. Pat. No. 5,968,952) is treated in a solvent suchas dimethylformamide (DMF) or tetrahydrofuran (THF) with a base such aspotassium carbonate. E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. The bromide isheated with triethylphosphite in a solvent such as toluene (or otherArbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988) to generate the diethyl esterof the desired phosphonic acid. Subsequently, the tertiary alcohol isconverted via the chloride to the amine using methods described inBioorg. Med. Chem. Lett., (2003), 13, 1543. The desired enantiomer isisolated by chromatography or by classical resolution using a chiralacid such as camphor sulfonic acid.

The N-methylquinolone (see U.S. Pat. No. 5,968,952, made by treating thestarting material in Scheme 29.3 with methyl iodide and potassiumcarbonate in a solvent such as DMF) is treated with the lithiatedimidazole shown (made from 1-(3-tetrahydropyranyloxy)propyl)imidazole bysuccessive treatment with n-butyl lithium, chlorotriethylsilane, andn-butyl lithium; see in Bioorg. Med. Chem. Lett., (2003), 13, 1543).After hydrolysis of the ether protecting group, the liberated primaryalcohol is treated in a solvent such as tetrahydrofuran ordimethylformamide with a base such as sodium hydride. When bubblingceases, diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477) is added, yielding the desiredphosphonate diester. Subsequently, the tertiary alcohol is converted viathe chloride to the amine using methods described in Bioorg. Med. Chem.Lett., (2003), 13, 1543. The desired enantiomer is isolated bychromatography or by classical resolution using a chiral acid such ascamphor sulfonic acid.

The primary amine is condensed with (2-oxo-ethyl)-phosphonic aciddiethyl ester under reductive conditions such as those achieved throughthe use of sodium cyanoborohydride in a solvent such as methanol ordimethylformamide (see Tet. Lett. (1990) 31, 5595).

The quinolone (see Bioorg. Med. Chem. Lett., (2003), 13, 1543) isN-methylated under standard conditions such as by treatment withiodomethane and potassium carbonate in DMF, and treatment with borontribromide liberates the phenol. This is alkylated as in Scheme 29.3above, and the subsequent steps are also analogous.

5-Chloro-1-pentyne is treated with triethylphosphite in a solvent suchas toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) to generate thediethyl ester of the desired phosphonic acid. This acetylene is coupledwith the bromo-containing analog of tipifarnib shown (made as in Bioorg.Med. Chem. Lett., (2003), 13, 1543, but starting from2-bromo-4-chloro-4′-nitrobenzophenone) under conditions such as thosepioneered by Sonagashira (Sonagashira, K.; Tohda, Y.; Hagihara, N.Tetrahedron Lett., (1975), 4467).

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the following section.

Example 30 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inSchemes 30.1-30.3, with examples depicted in Schemes 30.4-30.6.

The starting material (synthesis described in J. Med. Chem., (1999), 42,3494-3501) is treated in an organic solvent such as tetrahydrofuran(THF) or dichloromethane (DCM) with diethyl phosphonato ethylcarbaldehyde (1 equiv.) and sodium triacetoxyborohydride as described inJ. Org. Chem., (1996), 61, 3849-3862. The reaction is quenched withaqueous sodium bicarbonate and the product is extracted with an organicsolvent such as ethyl acetate. Drying and removal of the solvent yieldsthe crude product. Further purification is achieved by chromatography.

The product of this step is dissolved in trifluoroacetic acid (TFA) andis stirred at room temperature, according to J. Med. Chem., (1999), 42,3494-3501. At the end of the reaction, benzene is added and the solventsare removed in vacuo. The crude material is sufficiently pure for thenext step.

The crude material is dissolved in a mixture of N,N,N′,N′tetramethylethylenediamine, water andN-(β-hydroxyethyl)-N-(β-aminoethyl)amine, and the mixture is heated toreflux for several hours, according to a procedure from J. Med. Chem.,(1999), 42, 3494-3501. At the end of the reaction, chloroform is addedand the reaction mixture is washed with diluted aqueous hydrochloricacid and water and is dried. Removal of the solvents yields the crudeproduct. Further purification is achieved by chromatography.

Mitoxantrone is treated in an organic solvent such as THF or DCM withdiethyl phosphonato ethyl carbaldehyde (1 equiv.) and sodiumtriacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.Drying and removal of the solvent yields the crude product. Furtherpurification is achieved by chromatography.

The starting material (synthesis described in J. Med. Chem., (1999), 42,3494-3501) is treated in an organic solvent such as THF or DCM withchloroacetaldehyde (1 equiv.) and sodium triacetoxyborohydride asdescribed in J. Org. Chem., (1996), 61, 3849-3862. The reaction isquenched with aqueous sodium bicarbonate and the product is extractedwith an organic solvent such as ethyl acetate. Drying and removal of thesolvent yields the crude product. Further purification is achieved bychromatography.

The product of this step is dissolved in an organic solvent such asdimethylformamide or acetonitrile. 3-Aminopropyl phosphonic acid diethylester is added, followed by potassium carbonate and sodium iodide. Thereaction mixture is heated to an elevated temperature of ˜50-60° C. Atthe end of the reaction, the mixture is cooled to room temperature.Chloroform is added and the reaction mixture is washed with dilutedaqueous hydrochloric acid and water. Drying and removal of the solventsyields the crude product. Further purification is achieved bychromatography.

The product of this step is dissolved in trifluoroacetic acid (TFA) andis stirred at room temperature, according to J. Med. Chem., (1999), 42,3494-3501. At the end of the reaction, benzene is added and the solventsare removed in vacuo. The crude material is sufficiently pure for thenext step.

The crude material is dissolved in a mixture of N,N,N′,N′tetramethylethylenediamine, water, andN-(β-hydroxyethyl)-N-(β-aminoethyl) amine, and the mixture is heated toreflux for several hours, according to a procedure from J. Med. Chem.,(1999), 42, 3494-3501. At the end of the reaction, chloroform is addedand the reaction mixture is washed with diluted aqueous hydrochloricacid and water and is dried. Removal of the solvents yields the crudeproduct. Further purification is achieved by chromatography.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the following section.

Example 31 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can generally be prepared as described inSchemes 31.1-31.6, with examples depicted in Schemes 31.7-31.12.

2-Diethyl phosphonatoacetic acid is dissolved in an organic solvent suchas benzene, tetrahydrofuran (THF), or chloroform, is combined with atertiary amine base such as diisopropylethylamine (DIEA) and diphenylphosphorazidate (1.2 equiv) and is stirred at room temperature accordingto J. Med. Chem., (1991), 34, 1001-1018. After the acyl azide has beenformed, vindesine is added and the reaction mixture is heated to ˜80° C.for ˜4 hrs (Biochemistry (2002), 41, 14010-14018). The reaction mixtureis cooled to room temperature, washed aqueous HCl (1N) and aqueousbicarbonate solution and dried. Removal of the solvents yields the crudeproduct. Further purification is achieved by chromatography.

The starting material (synthesis published in J Med. Chem., (1978), 21,88-96; from vinblastine) is treated in an organic solvent such asdichloromethane (DCM) or THF with 2-aminoethylphosphonic acid diethylester at room temperature, according to the procedure described in J.Med. Chem., (1979), 22, 391-400. At the end of the reaction, thesolution is washed with water, aqueous bicarbonate and water, and isdried. Evaporation of solvents yields the crude product. Furtherpurification is achieved by chromatography.

2-Diethyl phosphonatoacetic acid is dissolved in an organic solvent suchas benzene, THF, or chloroform, and is combined with a tertiary aminebase such as diisopropylethylamine (DIEA) and diphenyl phosphorazidate(1.2 equiv) and stirred at room temperature according to J. Med. Chem.,(1991), 34, 1001-1018. After the acyl azide has been formed,N-1-(β-hydroxyethylthiomethyl)vinblastine (prepared according to Pearce,“Medicinal Chemistry of Bisindole Alkaloids from Catharanthus”, in TheAlkaloids, Vol. 37, 145, Academic Press San Diego, (1990), fromvinblastine via CrO₃-mediated oxidation in the presence of methanol andsubsequent methoxy displacement with β-hydroxythioethanol) is added, andthe reaction mixture is heated to ˜80° C. for ˜4 hrs (Biochemistry(2002), 41, 14010-14018). The reaction mixture is cooled to roomtemperature, washed with aqueous hydrochloric acid (HCl) (1N) andaqueous bicarbonate solution, and dried. Removal of the solvents yieldsthe crude product. Further purification is achieved by chromatography.

The product of this step is dissolved in an anhydrous organic solventsuch as methanol and dry liquid ammonia is added. The reaction mixtureis heated in sealed reaction vessel to an elevated temperature of ˜100°C., according to a procedure from J. Med. Chem., (1978), 21, 88-96. Atthe end of the reaction, the mixture is cooled to room temperature andthe solvents are removed in vacuo. Further purification is achieved bychromatography.

Vindesine and diethyl (cyanomethyl)phosphonate (commercially available)are dissolved in conc. sulfuric acid at a temperature of ˜0° C.,according to a procedure from Pearce, “Medicinal Chemistry of BisindoleAlkaloids from Catharanthus”, in The Alkaloids, Vol. 37, 145, AcademicPress San Diego, (1990) (described for acetonitrile). When the startingmaterial is consumed the reaction mixture is carefully diluted withwater and further neutralized. The crude reaction mixture is extractedwith an organic solvent such as DCM. The combined organic extracts arewashed with aqueous bicarbonate solution and dried. Removal of thesolvents yields the crude product. Further purification is achieved bychromatography.

C12′-Iodo-vinblastine (prepared according to Pearce, “MedicinalChemistry of Bisindole Alkaloids from Catharanthus”, in The Alkaloids,Vol. 37, 145, Academic Press, San Diego, (1990), by iodination ofvinblastine with ferrous perchlorate, tetra(n-propyl)ammoniumperiodinate and a catalytic amount of ruthenium dioxide) is added to amixture of copper(I) iodide and potassium phosphate and 2-aminoethylphosphonic acid diethyl ester (commercially available). The reactionmixture is heated under an inert gas atmosphere to ˜80° C., according toa procedure from Buchwald in Org. Lett., (2002), 4, 581-584. At the endof the reaction the material is cooled to room temperature and thesolvent is removed in vacuo. The crude reaction mixture is extractedwith an organic solvent such as DCM. The combined organic extracts arewashed with aqueous bicarbonate solution and dried. Removal of thesolvents yields the crude product. Further purification is achieved bychromatography.

The product of this step is dissolved in an anhydrous organic solventsuch as methanol and dry liquid ammonia is added. The reaction mixtureis heated in sealed reaction vessel to an elevated temperature of ˜100°C., according to a procedure from J. Med. Chem., (1978), 21, 88-96. Atthe end of the reaction the mixture is cooled to room temperature andthe solvents are removed in vacuo. Further purification is achieved bychromatography.

Vindesine is suspended in aqueous sodium hydroxide (5N) and is heated toreflux for several hours, according to Pearce, “Medicinal Chemistry ofBisindole Alkaloids from Catharanthus”, in The Alkaloids, Vol. 37, 145,Academic Press, San Diego, (1990) (described for vinblastine). At theend of the reaction, water is added and the reaction mixture isextracted with an organic solvent such as DCM or chloroform. Thecombined organic extracts are washed with brine and are dried. Removalof the solvent in vacuo yields the crude acid. Further purification isachieved by chromatography. The product of step 1 is dissolved in anorganic solvent such as DCM or dimethylformamide and the solution iscooled to −10° C. A tertiary amine base such as DIEA is added, followedby a coupling reagent such as iso-butylchloroformate. Stirring at −10°C. is continued until the activation is complete. Aminoethylphosphonicacid diethyl ester is added and stirring with slow warming to 0° C. iscontinued. At the end of the reaction, the solution is warmed to roomtemperature and the solvent is removed in vacuo. The product is furtherpurified by chromatography.

Example 32 Preparation of Exemplary Compounds of the Present Invention

5-Chloro-1-pentyne is treated with triethylphosphite in a solvent suchas toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press (1988) to generate thediethyl ester of the desired phosphonic acid. This acetylene is coupledwith lonafarnib under conditions such as those pioneered by Sonagashira(Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett., (1975),4467).

The piperazine shown (see J. Med. Chem., (1998), 41, 4890) is acylatedwith an activated diethylphosphonoacetic acid to provide the desiredamide linker compound, according to a procedure such as those reportedin J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27,600-604. The activated diethylphosphonoacetic acid is obtained bytreatment in a solvent such as dimethylformamide with a coupling reagentsuch as diethyl cyanophosphonate and a base such asdiisopropylethylamine at room temperature.

4-Allyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester iscoupled with 2-aminoethylphosphonic acid diethyl ester (commerciallyavailable) using standard reagents for the formation of a secondaryamide such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole(HOBT), in a solvent such as dimethylformamide. The olefin is oxidizedwith ozone to produce the carboxylic acid, which is then coupled withthe piperidine reagent shown (see J. Med. Chem., (1998), 41, 4890).Finally, the piperidine nitrogen is deprotected under standardconditions with trifluoroacetic acid, and the primary urea formed asdescribed in see J. Med. Chem., (1998), 41, 4890.

4-Carboxymethyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester(commercially available) is mono-protected by treatment with acidicmethanol. The remaining acid is coupled with 2-aminoethylphosphonic aciddiethyl ester (commercially available) using standard reagents for theformation of a secondary amide such as dicyclohexylcarbodiimide (DCC)and hydroxybenztriazole (HOBT), in a solvent such as dimethylformamide.The methyl ester is then saponified and coupled to the piperazine shown(see J. Med. Chem., (1998), 41, 4890). Finally, the piperidine nitrogenis deprotected under standard conditions with trifluoroacetic acid, andthe primary urea formed as described in see J. Med. Chem., (1998), 41,4890.

Example 33 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 33.1-33.4, with examples depicted in Schemes33.5-33.8.

Amsacrine can be treated in a solvent such as dimethylformamide (DMF),acetonitrile (MeCN), or dichloromethane (DCM) with excessiodotrimethylsilane, as described in Synthesis, (1985), 274. Afterquenching the reaction with aqueous sodium bicarbonate and extractingthe product with an organic solvent such as ethyl acetate, the freealcohol can be further purified by chromatography. This material is thentreated with tert-butoxycarbonyl anhydride in an organic solvent such asDMF and in the presence of a tertiary amine base such as pyridine (Greenand Wutts: Protective Groups in Organic chemistry). The solvent isremoved in vacuo and the product is further purified by chromatography.The alkoxide anion is then generated via treatment with sodium hydride(NaH) (˜1 equiv) in an organic solvent such as THF or DMF, and this isthen treated with diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477). When the starting material isconsumed, the reaction is quenched with water and the product isextracted with an organic solvent such as ethyl acetate. A finalchromatographic purification may be included. The tert-butoxycarbonylprotecting group is removed with trifluoroacetic acid (TFA) in DCMaccording to standard procedures (Green and Wutts: Protective Groups inOrganic chemistry).

Amsacrine is deprotonated by treatment with NaH (˜1 equiv) in an organicsolvent such as tetrahydrofuran (THF), and is then treated with diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) according to a procedure such as that reported in J.Med. Chem., (2000), 43, 489. When the starting material has beenconsumed, the reaction is quenched with water and the product isextracted with an organic solvent such as ethyl acetate. A finalchromatographic purification may be included.

2,5-Dinitrophenol is converted to the sodium salt in an appropriateorganic solvent such as THF, by treatment with NaH. The salt is thenreacted with carbon dioxide under Kolbe Schmitt conditions (J. Chem.Soc. (1954), 3145). The carboxylic acid product is then activated with asuitable coupling reagent such as isobutyl chloroformate in an organicsolvent such as DMF and in the presence of a tertiary amine base such asN,N-diisopropylethylamine (DIEA) at reduced temperatures of ˜−10° C. Theactivated intermediate is then reacted with 2-aminoethylphosphonic aciddiethyl ester and the reaction mixture is allowed to warm to 0° C. andthen to room temperature. The solvent is removed in vacuo, and the crudematerial is dissolved in an organic solvent such as ethyl acetate andwashed with diluted hydrochloric acid. The product is purified, asnecessary, by chromatography. The material is dissolved in an organicsolvent such as THF and is treated with sodium carbonate and methyliodide or dimethylsulfate. After the reaction is complete, the solidsare removed by filtration and the filtrate is concentrated in vacuo. Theproduct is purified, as necessary, by chromatography. This material isthen dissolved in a solvent such as ethyl acetate or DMF and ishydrogenated with the aid of Pd/C under an atmosphere of hydrogen. Thecrude reaction mixture is filtered through Celite and the solvent isremoved in vacuo. In case the product purity is not sufficient, furtherpurification can be achieved by chromatography. The amine is thenreacted in an organic solvent such as DMF in the presence of a tertiaryamine base such as DIEA with 9-chloroacridine according to J. Med. Chem.(1999), 42, 4741-4748. The solvent is removed in vacuo and the crudematerial is purified by chromatography. The product is then treated withmethanesulfonyl chloride in an organic solvent such as DCM or THF in thepresence of a tertiary amine base like DIEA. After removal of thesolvent, the final product is isolated by chromatography.

The starting material in Scheme 33.8 is available according to J. Med.Chem. (1999), 42, 4741-4748 via the reaction of the9-oxoacrididan-4-methyl-5-carboxylic acid chloride and2-aminoethylphosphonic acid diethyl ester. This material is then treatedwith thionyl chloride to yield the corresponding 9-chloroacridinederivative as described in the above reference. The crude material isthen dissolved in an organic solvent such as chloroform, DCM, or THF andtreated with 2-methoxy-4-nitroaniline. The crude product is isolated viaprecipitation and can be further purified by chromatography. Thismaterial is dissolved in an organic solvent such as DMF and is reducedin the presence of Pd/C under an atmosphere of hydrogen. Afterfiltration of the reaction mixture through Celite, the solvent isremoved in vacuo. The product can be purified further by chromatography.This material is then dissolved in an organic solvent such as THF orchloroform and is treated with methanesulfonyl chloride in the presenceof a tertiary amine base such as DIEA. After removal of the solvent, thefinal product is isolated by chromatography.

Example 34 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routesoutlined in Schemes 34.1-34.3, with examples depicted in Schemes34.4-34.6.

CEP-701 can be treated in a solvent such as dimethylformamide ortetrahydrofuran with two equivalents of a base such as sodium hydride.When bubbling ceases, benzyl bromide is added in excess, yielding thedoubly-protected intermediate. After further treatment with a base suchas magnesium tert-butoxide, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester. Final deprotection by hydrogenation over acatalyst such as palladium on charcoal in a solvent such as methanol asdescribed in Greene, T., Protective groups in organic synthesis,Wiley-Interscience, (1999), provides the desired product.

CEP-701 can be treated in a solvent such as dimethylformamide ortetrahydrofuran with one equivalent of a base such as sodium hydride orcesium carbonate. Benzyl bromide is added, yielding the N-benzylatedproduct. After further treatment with a base such as magnesiumtert-butoxide, diethyl phosphonomethyltriflate is added, yielding thedesired phosphonate diester. Final deprotection by hydrogenation over acatalyst such as palladium on charcoal in a solvent such as methanolutilizing the method described in Greene (see above) provides thedesired product.

(4-Formyl-phenoxymethyl)-phosphonic acid diethyl ester is generated bytreatment of 4-hydroxybenzaldehyde, in a solvent such asdimethylformamide or tetrahydrofuran, with a base such as sodium hydrideand diethyl phosphonomethyltriflate. The product is condensed withCEP-701 in a solvent such as toluene, in the presence of a catalyticamount of p-toluenesulfonic acid, with azeotropic removal of the waterso formed, yielding the desired acetal.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection

Example 35 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 35.1 and 35.3, with examples depicted in Schemes35.2 and 35.4.

The appropriately protected 5-aza-2′-deoxycytidine, prepared accordingto the procedure of Winkley, M. W., Robins, R. K., J. Org. Chem.,(1970), 35, 2, 491 (see also Ben-Hattar J., Jiricny, J. J. Org. Chem.,(1986), 51, 3211), can be treated in a solvent such as tetrahydrofuranor dimethylformamide with a base such as sodium hydride. Formation ofthe pivaloyl compound 35-1 can be accomplished by protecting5-aza-2′-deoxycytidine with a pivaloyl group (Greene, T., Protectivegroups in organic synthesis, Wiley-Interscience, (1999)). When bubblingceases, diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477) is added, yielding the protectedproduct. The pivaloyl group can be removed with sodium ethoxide toprovide the desired phosphonate diester 35-2, 35-3.

The preparation of compound 35-9 is described in Scheme 35.3. Compound35-15 may be the pivaloyl protected 5-aza-2′-deoxycytidine which isdescribed in Winkley, M. W., Robins, R. K., J. Org. Chem., (1970), 35,2, 491 and Ben-Hattar J., Jiricny, J., J. Org. Chem., (1986), 51, 3211.Protection of the 5′ hydroxyl group followed by protection of 2′ alcoholprovides compound 35-4. Removal of the 5′ protecting group provides thefree primary alcohol. Corey's one-step oxidation procedure (Corey, E. J.et al., J. Org. Chem., (1984), 49, 4735) can be utilized to transformthe primary alcohol to the ester 35-6. Deesterification, followed byoxidative decarbonylation using a modified Hunsdiecker reaction (Chu, C.K. et al., Tetrahedron Lett., (1991), 32, 3791) converts 35-7 to theacetate 35-8. The stereochemistry of the Vorbruggen glycosylation underLewis acid conditions is controlled by protecting group participation atthe 4′ position. A final deprotection provides the desired pro-drug35-9.

Specifically, compound 35-1 prepared by protection of5-aza-2′-deoxycytidine (prepared as in Winkley, M. W., Robins, R. K., J.Org. Chem., (1970), 35, 2, 491 and Ben-Hattar J., Jiricny, J. J. Org.Chem., (1986), 51, 3211 using pivaloyl chloride, can be protected with atert-butyldiphenylsilyl (TBDPS) group to provide the 5′-O-TBDPS analog.Further protection of the 3′ alcohol with the benzoyl group providescompound 35-10 (Teng, K., Cook, D. J. Org. Chem. (1994), 59, 278).Exposure of the fully protected compound 35-10 to HF-pyridine reagentselectively deprotects the 5′ hydroxyl group, which is then oxidized tothe t-butyl ester using the Corey-Samuelsson oxidation (Corey, E. J.,Samuelsson, B. J. Org. Chem., (1984), 49, 4735). Deesterification of theoxidized product using trifluoroacetic acid (TFA) provides compound35-12. Oxidative decarboxylation using a modified Hunsdiecker reaction(Chu, C. K. et al., Tetrahedron Lett., (1991), 32, 3791) converts thefree acid to the acetate 35-13 which may be a mixture of anomers at 5′.While separation of the anomers may be achieved by columnchromatography, it is not necessary to do so. The stereochemical outcomeof a Vorbruggen glycosylation is controlled by the stereochemistry ofthe 4′-benzoyl group due to anchimeric assistance, rendering separationof the isomers is unnecessary. Vorbruggen glycosylation usinghydroxymethylphosphonic acid diethyl ester proceeds to provide theprotected phosphonate. Final saponification to remove the pivaloate andthe benzoate groups completes the synthesis of compound 35-20 (Greene,T., Protective groups in organic synthesis, Wiley-Interscience, (1999)).

Example 36 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 36.1-36.2, with examples depicted in Schemes36.3-36.5.

The glucose derived starting material is synthesized from glucose and5-bromomethylthiophene-2-carbaldehyde (available from5-methylthiophene-2-carboxaldehyde and N-bromosuccinimide using aprocedure from Organikum, 17^(th) edition, page 167) according to themethods described in Chem. Lett., (1987), 799-802. The glycosidationreaction is performed with 4′-chloroacetyl-protected epipodophyllotoxin(described in the reference above) under catalysis of boron trifluoride(described in the reference above). The product of this reaction isdissolved in an organic solvent such as methanol and is treated withzinc acetate at reflux temperature. At the end of the reaction, themixture is cooled to room temperature and the solvent is removed invacuo. The crude reaction product is dissolved in an organic solventsuch as chloroform and the solution is washed with aqueous 0.1 M HCl andaqueous bicarbonate solution. After drying and removal of the solventthe crude product is obtained. Further purification is achieved bychromatography. The crude reaction product is dissolved in an organicsolvent such as dimethylformamide (DMF) or chloroform and is thentreated at a temperature of ˜40° C. with a base such as sodium carbonateand is reacted with aminoethyldiethylphosphonate. After all startingmaterial is consumed the reaction mixture is washed with aqueous 0.1 MHCl and aqueous bicarbonate solution. After drying and removal of thesolvent the crude product of the reaction is obtained. Furtherpurification is achieved by chromatography.

The starting material (synthesis according to Chem. Lett., (1987),799-804; from glucosamine and thiophene-2-carbaldehyde—commerciallyavailable) is treated in an organic solvent such as dichloromethane(DCM) or tetrahydrofuran (THF) with diethyl phosphonatoethylcarbaldehydeand sodium triacetoxyborohydride as described in J. Org. Chem., (1996),61, 3849-3862. The reaction is quenched with aqueous sodium bicarbonateand the product is extracted with an organic solvent such as ethylacetate. Further purification is achieved by chromatography.

The amine-containing starting material (obtained as described in J. Med.Chem., (1991), 34, 3346-3350) is treated in an organic solvent such asTHF or DCM with diethyl phosphonatoethylcarbaldehyde and sodiumtriacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.Further purification is achieved by chromatography.

All final products are converted to the corresponding 4′-phosphateanalogs via treatment of these compounds with phosphoryl trichloride inan organic solvent such as acetonitrile in the presence of an tertiaryorganic amine base such as N,N-diisopropylethylamine, followed bytreatment with aqueous bicarbonate solution as described in Bioorg. Med.Chem. Lett., (1994), 21, 2567-2572. Final product purification isachieved by chromatography.

Example 37 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routesoutlined in Schemes 37.1-37.5.

Staurosporin is acylated with activated benzoic acid derivatives such asbenzoyl chlorides in a solvent such as chloroform, in the presence of abase such as N,N-diisopropylethylamine (DIEA) (Bioorg. Med. Chem. Lett.,(1994), 4, 399). Examples of benzoyl chlorides for use in the synthesisof suitable phosphonate-containing midostaurin analogs are illustratedin Schemes 37.2-37.3 below.

4-Hydroxybenzoic acid methyl ester is treated with magnesiumtert-butoxide and diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477) in a solvent such astetrahydrofuran. The resulting 4-(diethoxyphosphorylmethoxy)benzoic acidmethyl ester is saponified with lithium hydroxide in ethanol, and theacid chloride is generated from the benzoic acid by reaction with oxalylchloride in a solvent such as dichloromethane, catalyzed bydimethylformamide.

3-Hydroxybenzoic acid methyl ester is treated in a solvent such asdimethylformamide or tetrahydrofuran with a base such as sodium hydride.When bubbling ceases, E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. The bromide isheated with triethylphosphite in a solvent such as toluene (or otherArbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988) to generate3-[4-(diethoxy-phosphoryl)-but-2-enyloxy]-benzoic acid methyl ester. Theremaining steps are similar to those described in Scheme 37.2.

Alkylations on the secondary amine of staurosporine have been carriedout under a variety of standard conditions: see Bioorg. Med. Chem.Lett., (1994), 4, 399. An example of the synthesis of aphosphonate-containing alkyl derivative is shown in Scheme 37.5.

Staurosporin is alkylated with diethyl phosphonomethyltriflate in thepresence of a base such as DIEA.

Example 38 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inSchemes 38.1 and 38.4 and Schemes 38.2, 38.3 and 38.5.

Introduction of the phosphonate-bearing entity at the quinazoline7-position is most conveniently achieved by alkylation of asuitably-protected 4-piperazinylquinazoline, prior to urea formation.

6,7-Dimethoxy-3,4-dihydroquinazolin-4-one is reacted with borontribromide to give a mixture of mono-demethylated products. Althoughthese may be separated by chromatography at this stage, the separationmay be more conveniently achieved on the mixture of acetates that arisesfrom reaction with and acetylating reagent such as acetyl chloride inthe presence of a base such as pyridine. The desired isomer is reactedwith thionyl chloride (see Bioorg. Med. Chem. Lett., (2001), 11, 1911)and the resulting 4-chloroquinazoline is treated withpiperazine-1-carboxylic acid benzyl ester. The acetyl protecting groupis removed under standard conditions such as by treatment with ammoniain methanol (see Greene, T., Protective groups in organic synthesis,Wiley-Interscience, (1999)) to generate Intermediate A.

Upon treatment with a base such as magnesium tert-butoxide and diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477), the phosphonate-bearing moiety is introduced at thequinazoline 7-position. Thereafter, removal of the benzyl carbamateprotecting group by hydrogenation over a catalyst such as palladium oncharcoal in a solvent such as methanol (see Greene, ibid) andcondensation with 4-isopropoxyaniline (commercially available) and4-nitrophenyl chloroformate provides the desired compound.

Intermediate A may be alkylated on the phenol by reaction with4-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester in thepresence of an azodicarboxylate diester such as diisopropylazodicarboxylate and triphenylphosphine, as described by Mitsunobu (BullChem. Soc. Japan., (1971), 44, 3427). Following deprotection withtrifluoroacetic acid, the liberated secondary amine is condensed with(2-oxo-ethyl)-phosphonic acid diethyl ester under reductive conditionssuch as those achieved through the use of sodium cyanoborohydride in asolvent such as methanol or dimethylformamide (see Tet. Lett. (1990),31, 5595). The remaining steps are similar to those described in Scheme38.2.

The route is similar to that shown in Schemes 38.1-38.3, but exploits aselective demethylation at the 6-position of6,7-dimethoxy-3,4-dihydroquinazolin-4-one (see Bioorg. Med. Chem. Lett.,(2001), 11, 1911). A specific example of such a synthesis is shown inScheme 38.5.

Following the selective demethylation, the steps are similar to thosediscussed in previous examples up to the point where a phenol isalkylated. In this example, however, the alkylation is performed withE-1,4-dibromobutene, and the monobromide product is reacted withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid. Thereafter, the steps are again similar to thosedescribed in previous examples.

Example 39 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inSchemes 39.1 and 39.3, with exemplifications in Schemes 39.2 and 39.4.

The coupling of an aniline with 2,3,4-trifluorobenzoic acid is performedin the presence of a large excess of a base such as lithiumdiisopropylamide in a solvent such as tetrahydrofuran, and attemperatures at or below ambient, as described in patent application WO2001-U.S. Pat. No. 22,948. The subsequent introduction of a phosphonatemoiety may be achieved by a variety of means, such as those illustratedScheme 39.2 below. Thereafter, the hydroxamic ester is generated bytreatment of the benzoic acid withO-(tetrahydro-2H-pyran-2-yl)hydroxylamine and diisopropylethylamine inthe presence of a coupling reagent such asbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) in a solvent such as tetrahydrofuran or dichloromethane, asdescribed in patent application WO 2000-U.S. Pat. No. 18,347 20000705,followed by treatment with ethanolic hydrochloric acid.

Having coupled 2,3,4-trifluorobenzoic acid with 2-iodo-5-nitroanisole(commercially available), the methyl ether is removed under standardconditions such as by treatment with hydrobromic acid in acetic acid(see Greene, T., Protective groups in organic synthesis,Wiley-Interscience, (1999)). The benzoic acid is esterified bydissolution in acidic methanol. The phenol is then treated in a solventsuch as tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester. Saponification of the benzoic acid (readyfor coupling to form the hydroxamate ester—see Scheme 39.1) is achievedwith lithium hydroxide in a solvent such as tetrahydrofuran or ethanol.

The iodo substituent present in PD-184352 may be used for theintroduction of a phosphonate-bearing moiety, as illustrated in Scheme39.4 below.

5-Chloro-1-pentyne is treated with triethylphosphite in a solvent suchas toluene (or other Arbuzov reaction conditions: see Engel, R.,Synthesis of carbon-phosphorus bonds, CRC press, 1988) to generate thediethyl ester of the desired phosphonic acid. This acetylene is coupledwith 39.5 under conditions such as those pioneered by Sonagashira(Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett., (1975),4467).

Example 40 Preparation of Exemplary Compounds of the Present Invention

Compounds can be prepared as generally described in Schemes 40.1-40.5,with specific examples depicted in Schemes 40.2-40.4. Final compounds,be they diastereoisomers or enantiomers, may be purified bychromatographic means.

In case a direct coupling to aminopterin is hampered by the presence ofa free secondary amine in the starting material (R=H), this entity willbe temporarily protected either with a tert-butoxycarbonyl group (R=Boc)or benzyloxycarbonyl (R=Cbz or Z) according to standard procedures(Green Wutts: Protective groups in organic chemistry).

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

When R=Z, the compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added. After consumption of the activated speciesis observed the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like. The intermediate isthen dissolved in a mixture of water, DMF, and acetic acid and istreated with hydrogen peroxide solution (excess). After removal of thesolvents the product is isolated via chromatography. Alternatively, theproduct can be isolated through precipitation from the reaction solutionwith an organic solvent such as diethyl ether or the like.

When R=Z, the compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604.).When the activation is complete,(L)-2-amino-6-(diethylphosphonato)-hexanoic acid is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the product is isolated via chromatography. Alternatively,the product can be isolated through precipitation from the reactionsolution with an organic solvent such as diethyl ether or the like.

When R=Z, the compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 4-amino-4-(diethylphosphonato)-butyric acidtert butylester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added.After consumption of the activated species is observed the solvent isremoved in vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventsuch as diethyl ether or the like.

When R=Z, the compound is dissolved in an organic solvent like DMF orNMP and a catalytic amount of Pd/C is added. The reaction mixture isstirred under an atmosphere of hydrogen until the starting material isconsumed. The Pd/C is removed and the solvent is evaporated in vacuo.The product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

Example 41 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be made according to the general routeoutlined in Scheme 41.1-41.5, with specific examples depicted in Schemes41.2-41.4. Final compounds, be they diastereoisomers or enantiomers, maybe purified by chromatographic means.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,2-aminoethylphosphonic acid diethyl ester (commercially available) isadded. After consumption of the activated species is observed thesolvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added. After consumption of the activated speciesis observed the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated via chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604.).When the activation is complete,(L)-2-amino-6-(diethylphosphonato)-hexanoic acid is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the product is isolated via chromatography. Alternatively,the product can be isolated through precipitation from the reactionsolution with an organic solvent like diethyl ether or the like.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 4-amino-4-(diethylphosphQnato)-butyric acidtert butylester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added.After consumption of the activated species is observed the solvent isremoved in vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventlike diethyl ether or the like

Example 42 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inScheme 42.1, with an example depicted in Scheme 42.2.

Preparation of a specific pro-drug of tacedinaline is shown in scheme42.1. The synthesis is planned so that attachment of the pro-drug moietyis performed late in the synthesis. Reduction of the nitro group allowsfor completion of the synthesis. A number of methods are reported inliterature for such a reduction; hydrogenation, Raney Nickel and tinchloride dihydrate are a few of these (Suzuki, T. et al., J. Med. Chem.,(1999), 42, 3001).

Preparation of a specific pro-drug linked tacedinaline is shown inScheme 42.2 in more detail. Compound 42-1 can be prepared according toU.S. Pat. No. 5,137,918. Compound 42-1 is treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester 42-2, 42-5. Reduction of the nitro group isaccomplished by hydrogenation or Raney Nickel conditions to provide thedesired pro-drug.

Example 43 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inScheme 43.1, with examples depicted in Scheme 43.2.

5-Nitro-isobenzofuran-1,3-dione (commercially available) is converted to5-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione following theprocedures reported in Bioorg. Med. Chem. Lett., (1999), 9, 1625. Thisamine intermediate is subjected to a reductive amination withdiethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallylphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog (J.Org. Chem., (1996), 61, 3849). Alternatively, the amine is acylated withan activated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., (1982), 25, 960 and J. Med. Chem., (1984), 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid (commerciallyavailable) is treated in a solvent such as acetonitrile withtriethylamine, 1-hydroxybenzotriazole, 4-methoxybenzylamine, and1,3-dicyclohexylcarbodiimide. After the reaction is complete, thesolvent is removed and the residue is purified by chromatography togenerate the desired analog, according to a procedure such as thatreported in J. Med. Chem., (2003), 46, 3793.

Example 44 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inScheme 44.1, with an example depicted in Scheme 44.2.

Synthesis of the pro-drug of TLK-286 is shown in Schemes 44.1 and 44.2.With two carboxylic acids present in the pro-drug moiety, mixtures ofcoupled product are separated by HPLC, to provide the desired product.Aminoethyl diethyl phosphonate is commercially available from Fluka asthe oxalate salt which can be freed using triethyl amine in the reactionmedium. Peptide coupling reactions are typically run indimethylformamide (DMF) with addition of dichloromethane. Carbodiimidecoupling reagents may be used in the presence of dimethylaminopyridineto speed up the reaction. Prevention of racemization may be achievedusing hydroxybenztriazole (HOBt).

Example 45 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inSchemes 45.1-45.2, with examples depicted in Scheme 45.3.

Pixantrone is treated in an organic solvent such as tetrahydrofuran(THF) or dichloromethane (DCM) with (2-oxoethyl)phosphonic acid diethylester (I equiv.) and sodium triacetoxyborohydride, as described in J.Org. Chem., (1996), 61, 3849-3862. The reaction is quenched with aqueoussodium bicarbonate and the product is extracted with an organic solventsuch as ethyl acetate. Separation of the product, the other regioisomer,and bis-alkylated material is achieved by chromatography.

Pixantrone is dissolved in an organic solvent such as dimethylformamide(DMF), THF, or chloroform and is treated with tert-butoxycarbonylanhydride according to standard literature procedures (Greene, T. W.:Protective groups in organic chemistry, Wiley-Interscience, (1999). Thesolvents are removed in vacuo. The crude material is dissolved in anorganic solvent such as chloroform and the solution is washed withaqueous 0.1 N HCl and aqueous bicarbonate solution. The solution isdried and the solvent is removed in vacuo. As needed the product isfurther purified by chromatography. The product of step 1 is dissolvedin an organic solvent such as DMF, and bromoacetic acid (1 equiv.) isadded. The solution is heated at an elevated temperature such as 50-70°C. under an atmosphere of an inert gas like nitrogen. When the reactionis complete, the solvent is removed in vacuo and the product is furtherpurified by chromatography. This material is dissolved in an organicsolvent such as chloroform or DMF and is reacted with2-aminoethylphosphonic acid diethyl ester (commercially available) inthe presence of a coupling reagent such as dicyclohexylcarbodiimide(DCC), an organic tertiary amine base such as diisopropylethylamine(DIEA), and a catalytic amount of N,N-dimethylaminopyridine (DMAP). Atthe end of the reaction, the reaction mixture is filtered and thesolvent is removed in vacuo. The crude material is dissolved in DCM andtreated with trifluoroacetic acid at room temperature according to thestandard (Greene, T. W.: Protective groups in organic chemistry,Wiley-Interscience (1999). At the end of the reaction the solvents areremoved in vacuo to yield the crude final product, which is furtherpurified by chromatography.

Example 46 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described inSchemes 46.1 and 46.3, with examples depicted in Schemes 46.2 and 46.4.

The appropriately protected 2′-deoxycoformycin prepared according toU.S. Pat. No. 3,923,785 (also reported in Chan, E. et al., J. Org.Chem., (1982), 47, 3457) can be treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.Formation of the fully protected compound 46-1, 46-3 can be accomplishedutilizing(8R)-6-(t-butoxycarbonyl)-8-[(t-butyldimethylsilyl)oxy]-3,6,7,8-tetrahedroimidazo[4,5-d]-[1,3]diazapine,prepared by Truong, T. V. et al. J. Org. Chem. (1993), 58, 6090, throughthe Vorbruggen glycosylation reaction as described in Chan, E. et al.,J. Org. Chem., (1982), 47, 3457. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester46-1, 46-3.

The preparation of compound 46-9 is described in Scheme 46.3. Compound46-1,(8-(tert-butyl-dimethyl-silanyloxy)-3-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-7,8-dihydro-3H-imidazo[4,5-d][1,3]diazepine-6-carboxylicacid tert-butyl ester) can be prepared as described in Truong, T. V. etal. J. Org. Chem., (1993), 58, 6090 and Chan, E. et al., J. Org. Chem.,(1982), 47, 3457. Oxidation of the 5′-OH followed by elimination of thecarboxylic acid provides glycal 46-5 (see the procedure of Zemlicka J.et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). Selenoetherificationprovides the protected phosphonate 46-6 (Kim, C. et al., J. Org. Chem.,(1991), 56, 2642). Oxidative elimination of the phenylselenide (asdescribed in Kim, C. et al., J. Org. Chem., (1991), 56, 2642) followedby stereoselective dihydroxylation provides the diol, which can then beconverted to a monotetrahydropyran protected compound 46-7. Acylation ofthe 2′ alcohol with phenyl chlorothionoformate provides the precursorfor Robins deoxygenation. Subsequent deoxygenation provides compound46-8 (Metteuci, M. D. et al. Tetrahedron Lett., (1987), 28, 22, 2459,also see Robins, M. J. et al. J. Org. Chem., (1995), 60, 7902). Theorder of formation of the 3′ protected alcohol and thiocarbonateformation can also be reversed if the first protection proceedsexclusively at the 2′ position. In that case, the 2′ thiocarbonate isformed first, followed by protection of the 3′ hydroxyl group and afinal Robins deoxygenation. Trifluoroacetic acid (TFA)-mediateddeprotection removed all three protecting groups to provide compound46-9.

Specifically, compound 46-3 (Truong, T. V. et al., J. Org. Chem.,(1993), 58, 6090 and Chan, E. et al., J. Org. Chem., (1982), 47, 3457)is oxidized with PtO₂ to provide carboxylic acid 2.2. Decarboxylativeelimination is achieved using dimethylformamide dineopentyl acetal inDMF at high temperature (Zemlicka J. et al., J. Am. Chem. Soc., (1972),94, 9, 3213). Once the furanoid glycal 46-11 is in hand, it is treatedwith phenylselenyl chloride to perform the selenoetherification followedby treatment with silver perchlorate in the presence ofdiethyl(hydroxymethyl)phosphonate (Phillion, D. et al., TetrahedronLett., (1986), 27, 1477) to give phosphonate 46-12 (Kim, C. et al., J.Org. Chem., (1991), 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides a diol,which is converted to the mono-protected tetrahydropyranyl ethercompound 46-13. Acylation of the 2′ alcohol with phenylchlorothionoformate provides the precursor for Robins deoxygenation,which is performed with tributyltin hydride to give compound 46-14(Metteuci, M. D. et al., Tetrahedron Lett., (1987), 28, 22, 2459, alsosee Robins, M. J. et al., J. Org. Chem., (1995), 60, 7902). Removal ofall the protecting groups is achieved using TFA to give compound 46-9(Greene, T., Protective groups in organic synthesis, Wiley-Interscience,(1999)).

Example 47 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routesoutlined in Schemes 47.1 and 47.3, with examples depicted in Schemes47.2 and 47.4.

TheN-(1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl)docosanamide(U.S. Pat. No. 3,991,045, also see Akiyama, M. et al., Chem. Pharm.Bull., (1978), 26, 3, 981) is treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester 47-2, 47-3.

The preparation of compound 47-9 is described in Scheme 47.3. Compound47-1 is prepared according to U.S. Pat. No. 3,991,045. Protection of the5′ hydroxyl group followed by protection of 2′ and 3′ alcohols providescompound 47-4. Removal of the 5′ protecting group provides the freeprimary alcohol precursor to the oxidation. Corey's one-step oxidationprocedure (Corey, E. J. et al., J. Org. Chem., (1984), 49, 4735) can beutilized to transform the primary alcohol to the ester 47-6.Deesterification followed by oxidative decarbonylation using a modifiedHunsdiecker reaction (Chu, C. K. et al., Tetrahedron Lett., (1991), 32,3791) converts 47-7 to the acetate 47-8. A Vorbruggen glycosylationusing Lewis acid conditions is controlled by the protecting groupparticipation at the 4′ position. A final deprotection provides thedesired prodrug 47-9.

Specifically, compound 47-1,N-(1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl)docosanamide(U.S. Pat. No. 3,991,045) is selectively protected with atert-butyldiphenylsilyl (TBDPS) group to provide the 5′-O-TBDPS analog.Further protection of the 3′ and 4′ alcohols as benzoate esters providescompound 47-10 (Teng, K., Cook, D. J. Org. Chem., (1994), 59, 278).Exposure of the fully protected compound 47-10 to HF-pyridine reagentselectively deprotects the 5′ hydroxyl group which can then be oxidizedto the t-butyl ester using the Corey-Samuelsson oxidation (Corey, E. J.,Samuelsson, B. J. Org. Chem., (1984), 49, 4735). Deesterification of theoxidized product using trifluoroacetic acid provides compound 47-13.Oxidative decarboxylation using a modified Hunsdiecker reaction (Chu, C.K. et al., Tetrahedron Lett., (1991), 32, 3791) converts the free acidto the acetate 47-14 which may be a mixture of anomers at 5′. Whileseparation of the anomers may be achieved by column chromatography, itis not necessary to do so. The stereochemical outcome of a Vorbruggenglycosylation is controlled by the stereochemistry of the 4′-benzoylgroup due to anchimeric assistance, rendering separation of the isomersis unnecessary. Vorbruggen glycosylation using hydroxymethylphosphonicacid diethyl ester proceeds to provide the protected phosphonate. Afinal deprotection using hydrolysis conditions completes the synthesisof compound 47-15.

Example 48 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these are made according to the general route outlinedin Schemes 48.1 and 48.3, with examples depicted in Schemes 48.2 and48.4.

The appropriately protected2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine48-1, prepared according to U.S. Pat. No. 5,034,518 (also described inWO 03011877) is treated in a solvent such as tetrahydrofuran ordimethylformamide with a base such as sodium hydride. Formation of thepivaloyl compound 48-1 is accomplished by protecting2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine witha pivaloyl group (Greene, T., Protective groups in organic synthesis,Wiley-Interscience, (1999)). When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the protected product 48-2, 48-3.The pivaloyl group is removed with sodium ethoxide to provide thedesired phosphonate diester 48-2, 48-3.

The preparation of compound 48-8 is described in Scheme 48.3. Compound48-4,9-(2-deoxy-α-D-ribofuranosyl)-2-fluoroadenine, is prepared asdescribed in Montgomery, J. et al., J. Med. Chem., (1969), 12, 3, 498.Oxidation of the 5′-OH followed by elimination provides glycal 48-5 (seethe procedure of Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9,3213). Protection of the chloroadenine at the 6 position followed byselenoetherification provides the protected phosphonate 48-6 (Kim, C. etal., J. Org. Chem., (1991), 56, 2642). Oxidative elimination of thephenylselenide (as described in Kim, C. et al., J. Org. Chem., (1991),56, 2642) followed by stereoselective dihydroxylation provides the diolwhich can then be converted to the 2′ protected alcohol. Protection ofthe 3′ alcohol followed by removal of the protecting group at the 2′hydroxyl group provides compound 48-7. Fluorination and inversion of thestereochemistry at the 2′ position can be simultaneously achieved byexposing the compound to dimethylaminosulfur trifluoroide (DAST) andpyridine (Pankiewicz, K. W. et al., J. Org. Chem., (1992), 57, 553, alsosee Pankiewicz, K. W. et al., J. Org. Chem., (1992), 57, 7315). Finally,the protecting groups are removed to provide compound 48-8.

Specifically, 9-(2-deoxy-α-D-ribofuranosyl)2-fluoroadenine, compound48-4 (Montgomery, J. et. al., J. Med. Chem., (1969), 12, 3, 498), isoxidized with PtO₂ to provide carboxylic acid 48-9. Decarboxylativeelimination is achieved using dimethylformamide dineopentyl acetal indimethylformamide at high temperature (Zemlicka J. et al., J. Am. Chem.Soc., (1972), 94, 9, 3213). Once the furanoid glycal 48-5 is in hand, itis first protected at the 6-position of the 2-chloroadenosine withpivaloyl chloride, using conditions as described in Greene, T.,Protective groups in organic synthesis, Wiley-Interscience, (1999).Treatment of the protected glycal with silver perchlorate in thepresence of diethyl(hydroxymethyl)phosphonate (Phillion, D. et al.,Tetrahedron Lett., (1986), 27, 1477) provides the phosphonate 48-10(Kim, C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative eliminationof the selenide followed by dihydroxylation using osmium tetraoxideprovides a diol which can be turned into a mono protected acetate 48-12by first silylating at the 2′-OH group, followed by protection of the 3′alcohol with an acetate group and subsequent deprotection of the silylgroup. Conversion of the 2′ alcohol to the 2′ fluoride with the oppositestereochemistry can be performed with DAST (Pankiewicz, K. W. et al., J.Org. Chem., (1992), 57, 553, also see Pankiewicz, K. W. et al., J. Org.Chem., (1992), 57, 7315). Conditions that deprotect the pivaloyl group(Greene, T., Protective groups in organic synthesis, Wiley-Interscience,(1999)) also remove the 3′ acetate to provide compound 48-13.

Example 49 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of the invention can be made according to thegeneral route outlined in Schemes 49.1 and 49.3, with examples depictedin Schemes 49.2 and 49.4.

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound49-1, 49-3, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, (2000), 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. (2003), 46, 3412) withBOC anhydride as described in Greene, T., Protective groups in organicsynthesis, Wiley-Interscience, (1999). Compound 49-1, 49-3 is thentreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester49-2, 49-4 after deprotection of the BOC group using trifluoroaceticacid (TFA).

The preparation of compound 49-16 is described in Scheme 49.3.Deprotected compound 49-5((1R)-1-(9-deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,as the hydrochloride salt) is prepared as described in Evans, G. B. etal., Tetrahedron, (2000), 56, 3053, using di-t-butyl dicarbonate indichloromethane. Oxidation of the 5′-OH followed by elimination providesglycal 49-6 (see the procedure of Zemlicka J. et al., J. Am. Chem. Soc.,(1972), 94, 9, 3213). Selenoetherification provides the protectedphosphonate 49-7 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642).Oxidative elimination of the phenylselenide (as described in Kim, C. etal., J. Org. Chem., (1991), 56, 2642) followed by stereoselectivedihydroxylation provides the desired diol 49-9. Finally, the protectinggroup is removed.

Specifically,(1R)-1-(9-deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,prepared as the HCl salt as described in Evans, G. B. et al.,Tetrahedron, (2000), 56, 3053, is first protected and then oxidized withPtO₂ to provide carboxylic acid 49-11. Decarboxylative elimination isachieved using dimethylformamide dineopentyl acetal in dimethylformamideat high temperature (Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94,9, 3213). Selenoetherification followed by treatment of the protectedglycal with silver perchlorate in the presence ofdiethyl(hydroxymethyl)phosphonate (Phillion, D. et al., TetrahedronLett., 1986, 27, 1477) provides the phosphonate 49-13 (Kim, C. et al.,J. Org. Chem., (1991), 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides diol 49-15.Removal of the amine protecting group, according to the procedure ofGreene, T., Protective groups in organic synthesis, Wiley-Interscience,(1999), provides compound 49-16.

Example 50 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be made according to the general routeoutlined in Schemes 50.2-50.4, with examples depicted in Schemes50.5-50.7.

10-Hydroxycamptothecin (prepared according to J. Org. Chem., (1995), 60,5739-5740 from camptothecin, which is commercially available) isdissolved in mixture of sulfuric acid and nitric acid under ice cooling.At the end of the reaction, the crude reaction solution is poured ontoice. The precipitate is collected and washed with water, cold ethanol,and diethyl ether. As needed the product is further purified byrecrystallization (J. Med. Chem., (2001), 44, 1594-602). The product ofstep 1 is dissolved in an organic solvent such as tetrahydrofuran (THF),acetonitrile, or dimethylformamide (DMF) and is treated with a base suchas sodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., (1986), 27, 1477) is added,yielding the desired phosphonate ester. The product is further purifiedby chromatography.

Rubetican is dissolved in an organic solvent such as DMF or ethylacetate and is hydrogenated in the presence of Pd/C under an atmosphereof hydrogen. At the end of the reaction, the crude suspension isfiltered through Celite and the solvent is removed in vacuo. As neededthe product is further purified by chromatography. The product of step 1is dissolved in an organic solvent such as THF, acetonitrile, or DMF andis treated with (2-oxoethyl)phosphonic acid diethyl ester (1 equiv.) andsodium triacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is collected as the resultant precipitate. The product isfurther purified by chromatography.

10-Hydroxycamptothecin is converted to the corresponding C7 aldehydeaccording to literature protocols (J. Med. Chem., (2000), 43,3963-3969). The product of this step is dissolved in an organic solventsuch as THF, acetonitrile, or DMF and is treated withaminoethylphosphonic acid diethyl ester (1 equiv.) and sodiumtriacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is purified by chromatography. The product of this step isdissolved in mixture of sulfuric acid and nitric acid under ice cooling.At the end of the reaction, the crude reaction solution is poured ontoice. The precipitate is collected and washed with water, cold ethanol,and diethyl ether. As needed the product is further purified byrecrystallization (J. Med. Chem., (2001), 44, 1594-602).

Further conversion to the C10 reduced product (according to J. Med.Chem., (1991), 34, 98-107).

The free C10 hydroxy compound synthesized above is dissolved in anorganic solvent such as DMF under an inert gas atmosphere. A tertiaryorganic amine base such as 2,6 lutidine is added, followed byN-phenyltrifluoromethanesulfonimide. The reaction mixture is stirred atroom temperature over night. When all starting material is consumed, asecond tertiary organic amine base such as triethylamine is addedfollowed by a palladium (II) species such as Pd(OAc)₂ and a phosphinesuch as triphenylphosphine, and concentrated formic acid. The reactionmixture is heated to an elevated temperature of approximately 60° C. Atthe end of the reaction, the solvent is removed in vacuo and the crudeproduct is triturated with a small amount of water and dried. Theproduct is further purified by chromatography.

Example 51 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of BAY-43-9006 which, upon cleavage insidethe target cell, give rise to agents with increased intracellularhalf-lives. Such compounds are described below.

Compounds such as these are made according to the general routesoutlined in Schemes 51.2, 51.4, 51.6 and 51.8, with specific examplesexemplified in Schemes 51.3, 51.5, 51.7 and 51.9.

The acid is coupled with 2-aminoethylphosphonic acid diethyl ester(commercially available) using standard reagents for the formation of asecondary amide such as dicyclohexylcarbodiimide (DCC) andhydroxybenztriazole (HOBT), in a solvent such as dimethylformamide.

An aniline bearing a phosphonate moiety is coupled with4-(4-aminophenoxy)-pyridine-2-carboxylic acid methylamide (U.S. PatentNo. 2002/0165394) in the presence of a reagent such as phosgene, in asolvent such as toluene to form a urea (see Bioorg. Med. Chem. Lett.,(2001), 11, 2775).

4-(4-Aminophenoxy)-pyridine-2-carboxylic acid methylamide is formed byalkylation of (4-hydroxypridine-2-carboxylic acid methylamide with4-fluoronitrobenzene with a base such as cesium carbonate in a solventsuch as dimethylformamide, followed by reduction of the nitro group withtin(II) chloride in a solvent such as ethanol.

The synthesis of a suitable phosphonate-bearing aniline is illustratedin Scheme 51.5.

2-Chloro-5-nitrophenol is alkylated with an excess ofE-1,4-dibromobutene in a solvent such as dimethylformamide in thepresence of a base such as potassium carbonate. The monobromide productis heated with triethylphosphite in a solvent such as toluene (or otherArbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988). Finally, the nitro group isreduced with tin(II) chloride in a solvent such as ethanol.

4-Chloro-3-trifluoromethylaniline is coupled with a4-phenoxy-substituted aniline bearing a phosphonate moiety in a mannersimilar to that shown in Scheme 51.4 to form a urea. The synthesis of asuitable phosphonate-bearing aniline is illustrated in Scheme 51.7.

(3-Benzyloxy)phenol is treated with magnesium t-butoxide and diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) in a solvent such as tetrahydrofuran. The benzyl groupis removed by hydrogenation over a catalyst such as palladium oncharcoal in a solvent such as methanol as described in Greene, T.,Protective groups in organic synthesis, Wiley-Interscience, (1999), andthe resulting phenol is alkylated with 4-fluoronitrobenzene with a basesuch as potassium carbonate in a solvent such as dimethylformamide.Finally, the nitro group is reduced as in Scheme 51.5.

4-Chloro-3-trifluoromethylaniline is coupled with a4-phenoxy-substituted aniline bearing a phosphonate moiety in a mannersimilar to that shown in Scheme 51.4 to form a urea. The synthesis of asuitable phosphonate-bearing aniline is illustrated in Scheme 51.9.

2-Chloro-5-nitrobenzoyl chloride is reacted with 2-aminoethylphosphonicacid diethyl ester. Thereafter, displacement of the chloride by reactionwith 4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide in thepresence of a base such as potassium carbonate in a solvent such astetrahydrofuran generates the biaryl ether motif, and reduction of thenitro group as in previous examples reveals the aniline ready forcoupling in the urea-forming step.

Example 52 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of SAHA which, upon cleavage inside thetarget cell, give rise to agents with increased intracellularhalf-lives. Such phosphonate pro-drug compounds are described below.

Compounds such as these are made according to the general route outlinedin Schemes 52.2 and 52.4, with specific examples depicted in Schemes52.3 and 52.5.

The synthesis of pro-drug 52-3, 52-13 is shown in Scheme 52.2 (WO118,171 and WO 03,032,921). A differentially-protected octanedioic acid(reported in U.S. Pat. No. 23,232) can be monodeprotected to provide52-6, 52-11. Coupling of the monoacid with 4-aminophenol using standardpeptide coupling conditions provides compound 52-7, 52-12. Hydrolysis ofthe remaining ester, followed by formation of the protected hydroxamide,gives compound 52-9. The phenolic moiety is utilized for attachment ofthe pro-drug unit late in the synthesis.

Specifically, octanedioic acid tert-butyl ester methyl ester ismonodeprotected using trifluoroacetic acid (TFA) to provide compound52-6, 52-11. Coupling of the free acid to 4-(methylamino)phenol (Nag, A.et al., Indian J. Chem. Sect. B., (1989), 64, 1 as well as U.S. Pat. No.2,397,911) provides amide 52-7, 52-12. Hydrolysis of the methyl estercan be achieved using LiOH to give the acid 52-8. Formation of theTBDPS-protected hydroxamic acid is performed by peptide couplingconditions using TBDPSO—NH₂, a carbodiimide such as EDC, andN—N-dimethylaminopyridine to form compound 52-9. Phenol 52-9 can betreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the protected phosphonate diester52-3, 52-13. Removal of the TBDPS group can be achieved using TFA toyield compound 52-3, 52-13.

Compound 52-4, 52-16, 52-17 can be prepared from the advancedintermediate 52-14 reported in WO 0118171. Protection of the hydroxamidefollowed by removal of the Cbz group provides compound 52-15, 52-19. Areductive amination using aldehyde 52-18, 52-20 (from Digital SpecialtyChemicals), followed by removal of the protecting group at thehydroxamide provides pro-drug 52-4, 52-16, 52-17.

The Cbz protected 52-14 can be prepared as described in WO 0118171.Blocking the hydroxamide using TBDPS (Greene, T., Protective groups inorganic synthesis, Wiley-Interscience, (1999)) followed by removal ofthe Cbz group provides compound 52-15, 52-19. The free amine of 52-15,52-19 can undergo a reductive amination with aldehyde 52-18, 52-20,available from Digital Specialty Chemicals (also reported in Olson, G.L. et al., J. Med. Chem., (1995), 38, 15, 2866) to form the pro-drug52-4, 52-16, 52-17.

Example 53 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of thalidomide which, upon cleavage insidethe target cell, give rise to agents with increased intracellularhalf-lives. Such compounds are described below.

Compounds such as these are made according to the general routesoutlined in Scheme 53.2, with examples depicted in Scheme 53.3.

2-Methyl-4-nitrobenzoic acid methyl ester (commercially available) isconverted to3-(5-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione,following the procedures reported in Bioorg. Med. Chem. Lett., (1999),9, 1625. This amine intermediate is subjected to a reductive aminationwith diethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallylphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog (J.Org. Chem., (1996), 61, 3849). Alternatively, the amine is acylated withan activated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., (1982), 25, 960 and J. Med. Chem., (1984), 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

2-Methyl-3-nitrobenzoic acid methyl ester (commercially available) istreated in a solvent such as carbon tetrachloride withN-bromosuccinimide under light to produce 2-bromomethyl-3-nitrobenzoicacid methyl ester. This benzylic bromide is treated in a solvent such asdimethylformamide with[2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester (for the preparation of this compound, see below) in the presenceof a base such as triethylamine. The coupled product is then reduced byhydrogenation (Bioorg. Med. Chem. Lett., (1999), 9, 1625) to afford thedesired analog. [2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonicacid diethyl ester is obtained according to a procedure such as thatreported in J. Med. Chem., (2003) 46, 3793. Accordingly,benzyloxycarbonyl-protected glutaric acid is treated in a solvent suchas acetonitrile with triethylamine, 1-hydroxybenzotriazole, diethyl2-aminoethylphosphonate and 1,3-dicyclohexylcarbodiimide. After thereaction is complete, the solvent is removed and the residue is purifiedby chromatography to generate the cyclic product, which is subjected tohydrogen in the presence of palladium catalysis to afford the desiredintermediate.

Example 54 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy are achieved by theuse of pro-drugs of analogs of MS-275 which, upon cleavage inside thetarget cell, gives rise to agents with increased intracellularhalf-lives. Such phosphonate pro-drug compounds are described below.

Compounds such as these are made according to the general route outlinedin Scheme 54.2, with an example depicted in Scheme 54.3.

Preparation of a pro-drug of MS-275 is shown in Scheme 54.2. Compound54-4 (prepared according to CH 569714 as well as Chem Abstr. 78, 16049)is transformed to the carbamate 54-5 through activation of the alcoholby formation of a carbonyl imidazole intermediate, followed by additionof 4-(aminomethyl)benzoic acid. Subsequent coupling of the carboxylicacid of 54-5 with 2-aminoaniline proceeds to provide compound 54-6.Hydrolysis of the ester followed by coupling of the acid with the aminophosphonate pro-drug completes the synthesis of pro-drug 54-2.

Preparation of the pro-drug linked MS-275 is shown in Scheme 54.3 inmore detail. Compound 54-7 is prepared according to reported methods (CH569714 as well as Chem Abstr. 78, 16049). Condensation of 54-7 with4-(aminomethyl)benzoic acid (from Aldrich) using1,1′-carbonyldiimidazole gives carboxylic acid 54-8 (Suzuki, T. et al.,J. Med. Chem., (1999), 42, 3001). Acid 54-8 is converted into acylchloride by treatment with oxalyl chloride, followed by reaction withimidazole to form the acylimidazole intermediate. This is then reactedwith 2-aminoaniline in the presence of trifluoroacetic acid (TFA) toform 54-9. Hydrolysis of the methyl ester followed by coupling withdiethyl aminoethylphosphonate (from Fluka) gives pro-drug 54-10.

Formation of the pro-drug 54-3 follows analogous procedures to thosedescribed above. The starting material, 5-hydroxymethylnicotinic acidmethyl ester, can be prepared according to Hemel J. V. et al.,Nucleosides Nucleotides, (1996), 15, 1203. The subsequent steps are asshown in Scheme 54.3.

Example 55 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of the invention are made according to thegeneral route outlined in Scheme 55.1, with an example depicted inScheme 55.2.

Preparation of pro-drug 55-7 is shown in Scheme 55.1. Compound 55-1,4-formylcinnamic acid is first esterified to provide aldehyde 55-2 (WO03039599). The aldehyde undergoes a reductive amination with3-(2-aminoethyl)-1H-indol-5-ol (available from Aldrich) to providecompound 55-3. Alkylation of the secondary amine in 55-3 using aprotected 2-bromoethanol provides compound 55-4. Phenol 55-4 can betreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride.

When bubbling ceases, a dialkyl phosphonate such as diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester55-5. Formation of the N-hydroxy amide is performed using hydroxylaminein base to provide compound 55-6. Final removal of the protecting groupon the primary alcohol provides the pro-drug 55-7.

A detailed synthesis of pro-drug of LAQ-824 is demonstrated in Scheme55.2 4-formylcinnamic acid is first esterified to provide methyl ester52-14 (WO 03039599). The aldehyde of 52-14 undergoes a reductiveamination with 3-(2-aminoethyl)-1H-indol-5-ol (available from Aldrich)to provide amine 55-8. Alkylation of the amine with(2-bromoethoxy)-tert-butyldimethylsilane yields compound 55-9.Alkylation of the phenol 55-9 with phosphonomethyl triflate yieldsphosphonate 55-10. Formation of N-hydroxy amide takes place usinghydroxylamine in a basic reaction medium. A final TBDMS removal givesthe pro-drug 55-12.

Other syntheses can follows the same synthetic path illustrated above,for example, using 1H-indol-6-ol (available from Toronto ResearchChemicals) as the corresponding starting material.

Example 56 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routeoutlined in Schemes 56.1 and 56.3, with examples depicted in Schemes56.2 and 56.4.

The arabinofuranosyl-2-fluoroadenine 56-1 (prepared according to theprocedure of Montgomery, J. et al., J. Med. Chem., (1969), 12, 3, 498)is treated in a solvent such as tetrahydrofuran or dimethylformamidewith a base such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester56.2.

Preparation of compound 56-8 is described in Scheme 56.3. Compound 56-4(9-(2-deoxy-α-D-ribofuranosyl)-2-fluoroadenine) is prepared as describedin Montgomery, J. et. al., J. Med. Chem., (1969), 12, 3, 498 as well asU.S. Pat. No. 4,210,745. Oxidation of the 5′-OH followed by eliminationprovides glycal 56-5 (see the procedure of Zemlicka J. et al., J. Am.Chem. Soc., (1972), 94, 9, 3213). Protection of the fluoroadenine at the6 position followed by selenoetherification provides the protectedphosphonate 56-6 (Kim, C. et al., J. Org. Chem., (1991), 56, 2642).Oxidative elimination of the phenylselenide (as described in Kim, C. etal., J. Org. Chem., (1991), 56, 2642) followed by stereoselectivedihydroxylation provides the diol which is converted to a monotriflate.Protection of the 3′ alcohol provides compound 56-7. Conversion of thestereochemistry at the 2′ position is achieved by exposing the compoundto LiOAc to provide the protected desired stereoisomer of the product.Finally, the protecting groups are removed.

Specifically, 9-(2-deoxy-α-D-ribofuranosyl)2-fluoroadenine, compound56-4, (Montgomery, J. et. al., J. Med. Chem., (1969), 12, 3, 498 as wellas U.S. Pat. No. 4,210,745) is oxidized with PtO₂ to provide carboxylicacid 56-9. Decarboxylative elimination is achieved usingdimethylformamide dineopentyl acetal in DMF at high temperature(Zemlicka J. et al., J. Am. Chem. Soc., (1972), 94, 9, 3213). Once thefuranoid glycal 56-5 is in hand, it is first protected at the 6-positionof the 2-fluoroadenosine using PivCl conditions as described in Greene,T., Protective groups in organic synthesis, Wiley-Interscience, (1999).Treatment of the protected glycal with silver perchlorate in thepresence of diethyl(hydroxylmethyl)phosphonate (Phillion, D. et al.,Tetrahedron Lett., 1986, 27, 1477) provides the phosphonate 56.10 (Kim,C. et al., J. Org. Chem., (1991), 56, 2642). Oxidative elimination ofthe selenide followed by dihydroxylation using osmium tetraoxideprovides a diol which can be turned into a mono protected triflate56-12. Reversal of configuration of the 2′ alcohol can be achieved byreplacement of the triflate with an acetate group. Deprotection of thepivaloyl group (Greene, T., Protective groups in organic synthesis,Wiley-Interscience, (1999)) removes the newly installed 2′ acetate aswell. A final deprotection of the THP group can be achieved in acidicmedia.

Example 57 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention is prepared as generally described in Scheme57.1, with an example depicted in Scheme 57.2.

Preparation of the compound is achieved via reductive amination of aphosphonate-containing aldehyde using Pirarubicin itself. Such aldehydescan be prepared according to Synth. Commun. (1992), 22, 2219.

Example 58 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention are prepared as generally described in thefollowing Schemes.

Daunorubicin is protected on the aminosugar moiety using a Cbzprotecting group as described in Greene, T., Protective groups inorganic synthesis, Wiley-interscience publication, (1999) to generate58-7. The alcohol is treated in a solvent such as dichloromethane,tetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester 58-6 after purification. Final deprotectionby hydrogenation over a catalyst such as palladium on charcoal conditionin a solvent such as methanol utilizing the method of Greene et. al.provides the desired product.

Alkyl derivatives of the aminosugar nitrogen have been reported(Farquhar, D. et. al., J. Med. Chem., (1998), 41, 6, 965). Attachment ofthe phosphonate prodrug moiety onto this amine via alkylation is shownin Scheme 58.3. A specific example of the preparation of 58-9 isprovided in Scheme 58.4.

Preparation of the prodrug 58-9 is achieved via reductive amination of aphosphonate-containing aldehyde using Daunorubicin itself. Suchaldehydes are prepared according to Synth. Commun. (1992), 22, 2219.

Further manipulations may be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described below.

Example 59 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of formulae 59-4, 59-7 can be made according tothe general route outlined in Scheme 59.1, with an example depicted inScheme 59.2.

Idarubicin is protected on the aminosugar moiety using a Cbz protectinggroup as described in Greene, T., Protective groups in organicsynthesis, Wiley-interscience publication, (1999) to generate 59-5. Thealcohol is treated in a solvent such as dichloromethane, tetrahydrofuranor dimethylformamide with a base such as sodium hydride. When bubblingceases, diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., (1986), 27, 1477) is added, yielding the desiredphosphonate diester 59-6 after purification. Final deprotection byhydrogenation over a catalyst such as palladium on charcoal condition ina solvent such as methanol utilizing the method of Greene et. al.provides the desired product.

Alkyl derivatives of the aminosugar nitrogen have been reported(Farquhar, D. et. al., J. Med. Chem., (1998), 41, 6, 965). Attachment ofthe phosphonate prodrug moiety onto this amine via alkylation is shownin Scheme 59.3. A specific example of the preparation of 59-9 isprovided in Scheme 59.4.

Preparation of the prodrug 59-9 is achieved via reductive amination of aphosphonate-containing aldehyde using Idarubicin itself. Such aldehydesare prepared according to Synth. Commun. (1992), 22, 2219.

Example 60 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of the invention can be made according to thegeneral route outlined in Schemes 60.1-60.3, with examples depicted inSchemes 60.4-60.6.

Exatecan is dissolved in an organic solvent such as tetrahydrofuran(THF), acetonitrile, or dimethylformamide (DMF) and is treated(2-oxo-ethyl)-phosphonic acid diethyl ester (1 equiv.) and sodiumtriacetoxyborohydride as described in J. Org. Chem., ((1996)), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.The product is further purified by chromatography.

Exatecan is dissolved in an organic solvent such as carbontetrachloride. N-Bromo succinimide (NBS) is added followed byazobisisobutyronitrile (AIBN), according to a procedure from Organikum,17^(th) edition, Deutscher Verlag der Wissenschaften, (1988), 167. Thereaction is heated to reflux temperature for a few hours. At the end ofthe reaction the mixture is cooled to room temperature. The reaction isfiltered and the solvent is removed in vacuo, yielding the crudeproduct. Further separation from regioisomeric products is achieved bychromatography.

The product of step 1 is dissolved in an organic solvent such asacetonitrile or DMF and is treated with aminoethylphosphonic aciddiethyl ester (excess), sodium iodide (1 equiv), and sodium carbonate (1equiv). The reaction mixture is heated to an elevated temperature of˜50-60° C. At the end of the reaction, the mixture is cooled to roomtemperature and is filtered. The crude reaction product is dissolved inan organic solvent such as dichloromethane (DCM), chloroform or benzeneand the solution is washed with aqueous hydrochloric acid (HCl) (0.1N),and dried. Filtration and removal of the solvent in vacuo yields thecrude product. The product is further purified by chromatography.

Exatecan is dissolved in an organic solvent such as DMF, DCM, oracetonitrile. Tert. butoxycarbonyl anhydride is added, followed by acatalytic amount of 4-dimethylaminopyridine (DMAP) (Green and Wuts,Protective Groups in Organic Synthesis, Wiley and Sons, NY, (1999)).Stirring at room temperature is continued. At the end of the reaction,water is added and the crude reaction mixture is extracted with anorganic solvent such as DCM or chloroform and dried. Removal of thesolvents yields the crude product. Further purification is achieved bychromatography.

The product of step 1 is dissolved in an organic solvent such as THF,DMF, or chloroform and is treated with aqueous sodium hydroxide (NaOH).Stirring at room temperature is continued until conversion to the openedlactone is observed. The solvent is removed in vacuo and the crudematerial is dissolved in an organic solvent such as methanol or DMF.Aminoethylphosphonic acid diethyl ester is added and the reaction isheated to reflux for an extended period of time, according to amodification of the procedure from J. Am. Chem. Soc., (1957), 79,385-391. At the end of the reaction, the mixture is cooled to roomtemperature and is acidified with aqueous HCl. Stirring is continueduntil formation of the lactone is observed, according to J. Am. Chem.Soc., (1966), 88, 3888-3890. The solvents are removed in vacuo and themixture is partitioned between an organic solvent such as chloroform orDCM and aqueous HCl (0.1N). The organic layer is isolated and thesolvent is removed in vacuo. The crude material is dissolved in anorganic solvents such as DCM or chloroform and is treated withtrifluoroacetic acid (TFA) (Green and Wuts, Protective Groups in OrganicSynthesis, Wiley and Sons, NY, (1999)). At the end of the reaction,solid sodium bicarbonate is added and the reaction is filtered. Thesolvents are removed in vacuo. Further product purification is achievedby chromatography.

Example 61 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of the invention can be made according to thegeneral route outlined in Schemes 61.1-61.3, with examples depicted inSchemes 61.4-61.6.

Synthesis of the Aromatic Starting Material (1):

2-Cyanophenylbromide (commercially available) is dissolved in an organicsolvent such as N-methylpyrrolidinone (NMP) or dimethylformamide (DMF),under an inert gas atmosphere. Sodium carbonate, triphenylphosphine, andmethyl acrylate are added, followed by palladium (II) acetate(Pd(OAc)₂). The reaction mixture is heated to an elevated temperature of˜100-140° C., according to procedures from Chem. Rev., (2000), 100,3009. At the end of the reaction, the reaction mixture is cooled to roomtemperature, and filtered through Celite. Removal of solvents yields thecrude product. Further purification is achieved by chromatography.

The crude material from step one is dissolved in a mixture of organicsolvents such as benzene and ethanol under an inert gas atmosphere.Wilkinson's catalyst [RhCl(PPh₃)₃] is added and the reaction mixture isplaced under an hydrogen atmosphere of ˜60-80 psi and is heated to anelevated temperature of ˜60° C., according to the procedure described inJ. Org. Chem., (1969), 34, 3684-3685. At the end of the reaction, thereaction mixture is cooled to room temperature and the solvents areremoved in vacuo. The crude material is triturated with diethylether,and the catalyst is removed by filtration through Celite. Removal of thesolvent yields the crude material. Further purification is achieved bychromatography.

The crude material of step 2 is dissolved is dissolved in polyphosphoricacid and is heated to an elevated temperature of 90° C. under an intergas atmosphere, according to a procedure from Org. Lett., (2001), 3,279-281. At the end of the reaction, the mixture is cooled to roomtemperature and is poured onto ice and extracted with an organic solventsuch as diethylether. The combined organic extracts are washed withbrine and dried. Removal of the solvent yields the crude product.Further purification is achieved by chromatography.

Synthesis of the Guanidine Derivative (2):

Di(imidazol-1-yl)methanimine is dissolved in an organic solvent such astetrahydrofuran (THF), and is reacted with 2-aminoethyl phosphonic aciddiethyl ester at room temperature, according to the procedure describedin J. Org. Chem., (2002), 67, 7553-7556. At the end of the reaction,water is added and the product is extracted with an organic solvent suchas dichloromethane (DCM). The combined organic layers are washed withsaturated aqueous ammonium chloride solution, water and brine, anddried. Removal of the solvents yields the crude material. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such as DMFand reacted with hydrazine at an elevated temperature of ˜100° C. in asealed vessel, according to a slightly modified procedure from thereference cited above. At the end of the reaction, the mixture is cooledto room temperature and water is added. The product is extracted with anorganic solvent such as DCM. The combined organic layers are washed withsaturated aqueous ammonium chloride solution, water and brine, anddried. Removal of the solvents yields the crude material. Furtherpurification is achieved by chromatography.

Final Elaboration (3):

The products of reaction sequence (1) and (2) are dissolved in anorganic solvent such as ethanol and treated with a catalytic amount ofconcentrated sulfuric acid. This mixture is heated to reflux for aminimal amount of time, as described in J. Med. Chem., (1993), 36,46-54. The reaction mixture is cooled to room temperature and thesolvent is removed in vacuo. The product is dissolved in an organicsolvent such as ethylacetate or chloroform and is washed with water. Theorganic layer is dried and the solvent is removed in vacuo. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in a mixture of organic solventssuch as diethyl ether and ethanol. The solution is saturated withhydrochloric acid gas at 0° C. and is kept at this temperature for anextended period of time. At the end of the reaction productprecipitation is induced by the addition of diethyl ether. Theprecipitate is collected and dried in vacuo. The crude material isdissolved in an organic solvent such as ethanol and ammonium saturatedethanol is added. The mixture is heated to an elevated temperature of˜70° C. for several hours. At the end of the reaction, the mixture iscooled to room temperature and the solvents are removed in vacuo. Theproduct is further purified either by recrystallization fromethanol/diethylether mixtures or by chromatography.

Synthesis of the Guanidine Derivative (11.

Tert. butyl earbazate (commercially available) is treated in an organicsolvent such as DCM or THF with diethyl phosphonatoethylcarbaldehyde andsodium triacetoxyborohydride as described in J. Org. Chem., (1996), 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.Further purification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such as THF,and is reacted with di(imidazol-1-yl)methanimine, according to theprocedure described in J. Org. Chem., (2002), 67, 7553-7556. At the endof the reaction, water is added and the product is extracted with anorganic solvent such as DCM. The combined organic layers are washed withsaturated aqueous ammonium chloride solution, water, brine and aredried. Removal of the solvents yields the crude material. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such as DMFand reacted with ammonia at an elevated temperature of ˜100° C. in asealed vessel, according to a slightly modified procedure from thereference cited above. At the end of the reaction, the mixture is cooledto room temperature and water is added. The product is extracted with anorganic solvent such as DCM. The combined organic layers are washed withsaturated aqueous ammonium chloride solution, water and brine, and aredried. Removal of the solvents yields the crude material. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in an organic solvent such as DCMand is treated with trifluoroacetic acid (TFA), according to a procedurefrom Green and Wuts, Protective Groups in Organic Synthesis. At the endof the reaction sodium bicarbonate is added and the reaction mixture isfiltered. Removal of the solvents in vacuo yields the crude product.Further purification is achieved by chromatography.

Final Elaboration (3):

The products of the above reactions are dissolved in an organic solventsuch as ethanol and treated with a catalytic amount of concentratedsulfuric acid. This mixture is heated to reflux for a minimal amount oftime, according to the procedure described in J. Med. Chem., (1993), 36,46-54. The reaction mixture is cooled to room temperature and thesolvent is removed in vacuo. The product is dissolved in an organicsolvent such as ethyl acetate or chloroform and is washed with water.The organic layer is dried and the solvent is removed in vacuo. Furtherpurification is achieved by chromatography.

The product of this step is dissolved in a mixture of organic solventssuch as diethyl ether and ethanol. The solution is saturated withhydrochloric acid gas at 0° C. and is kept at 0° C. for an extendedperiod of time. At the end of the reaction product precipitation isinduced by the addition of diethylether. The precipitate is collectedand dried in vacuo. The crude material is dissolved in an organicsolvent such as ethanol and ammonium saturated ethanol is added. Themixture is heated to an elevated temperature of ˜70° C. for severalhours. At the end of the reaction, the mixture is cooled to roomtemperature and the solvents are removed in vacuo. The product isfurther purified either by recrystallization from ethanol/diethyl ethermixtures or by chromatography.

The product of sequence (1) in Scheme 61.4 is dissolved in an organicsolvent such as THF and the solution is cooled to −78° C. Lithiumdiisopropylamide solution is added, and the reaction mixture is stirredfor a few minutes. When the deprotonation is complete, E-1,4dibromobutene is added in excess and the reaction is allowed to warm toroom temperature. The reaction is quenched with aqueous ammoniumchloride solution and the product is extracted with an organic solventsuch as ethyl acetate or chloroform. Drying and removal of solventsyields the crude product. Further purification is achieved bychromatography.

The product of this step is heated with triethylphosphite in an organicsolvent such as toluene to an elevated temperature of 110° C., accordingto procedures outlined in Engel, R., Synthesis of carbon phosphorusbonds, CRC press (1988). At the end of the reaction, the mixture iscooled to room temperature and the solvents are removed in vacuo,yielding the crude product. Further purification is achieved bychromatography.

The product of this reaction and aminoguanidine are dissolved in anorganic solvent such as ethanol and treated with a catalytic amount ofconcentrated sulfuric acid. This mixture is heated to reflux for aminimal amount of time, according to a procedure from J. Med. Chem.,(1993), 36, 46-54. The reaction mixture is cooled to room temperatureand the solvent is removed in vacuo. The product is dissolved in anorganic solvent such as ethyl acetate or chloroform and is washed withwater. The organic layer is dried and the solvent is removed in vacuo.Further purification is achieved by chromatography.

The product of this step is dissolved in a mixture of organic solventssuch as diethyl ether and ethanol. The solution is saturated withhydrochloric acid gas at 0° C. and is kept at 0° C. for an extendedperiod of time. At the end of the reaction, product precipitation isinduced by the addition of diethyl ether. The precipitate is collectedand dried in vacuo. The crude material is dissolved in an organicsolvent such as ethanol and ammonium saturated ethanol is added. Themixture is heated to an elevated temperature of ˜70° C. for severalhours. At the end of the reaction, the mixture is cooled to roomtemperature and the solvents are removed in vacuo. The product isfurther purified either by recrystallization from ethanol/diethyl ethermixtures or by chromatography.

Further manipulations are performed on the phosphonate moiety prior tothe final deprotection. These types of transformations are moreextensively described in the following section.

Example 62 Preparation of Exemplary Compounds of the Present Invention

Representative compounds of formulae 62-4, 62-7 are made according tothe general route outlined in Scheme 62.1, with an example depicted inScheme 62.2.

Adriamycin is protected on the aminosugar moiety using a Cbz protectinggroup as described in Greene, T., Protective groups in organicsynthesis, Wiley-interscience publication, (1999). Protection of theprimary alcohol to prepare 62-5 using the acetate protecting group hasbeen described (U.S. Pat. No. 4,303,785). The alcohol is treated in asolvent such as dichloromethane, tetrahydrofuran or dimethylformamidewith a base such as sodium hydride. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate diester62-6 after purification. Final deprotection by hydrogenation over acatalyst such as palladium on charcoal condition in a solvent such asmethanol utilizing the method of Greene et al. followed by exposure ofthe compound to potassium carbonate provides the desired product.

Alkyl derivatives of the aminosugar nitrogen have been reported(Farquhar, D. et. al., J. Med. Chem., (1998), 41, 6, 965). Attachment ofthe phosphonate prodrug moiety onto this amine via alkylation is shownin Scheme 623. A specific example of the preparation of 62-9 is providedin Scheme 62.4.

Preparation of the prodrug 62-9 is achieved via reductive amination of aphosphonate-containing aldehyde using Adriamycin itself. Such aldehydesare prepared according to Synth. Commun. (1992), 22, 2219.

Example 63 Preparation of Exemplary Compounds of the Present InventionBackground and Utility of Scaffold Compound

Certain triaryl ethylenes are useful in the treatment ofhypercholesterolemia and osteoporosis by acting as selective estrogenreceptor modulators. One such derivative, Ospemifene, is described inWO01/36360 page 3 line 5. The present invention provides novel analogsof Ospemifene, 63-1. Such novel Ospemifene analogs, as described bystructures 63-2, 63-3, and 63-4, possess all the utilities of AGI-1067and optionally provide cellular accumulation as set forth below.

Method of Making New Compound:

The synthesis of Ospemifene, 63-1 is described in WO01/36360. As shownin Schemes 63.1-63.2, compound 63-1 is treated with adialkylphosphonoalkyltrifluoromethylsulphonate in a solvent such aspyridine or a non basic solvent such as dichloromethane containing abase such as triethylamine to furnish the ether of 63-1. The alkylgroups are removed from the phosphonate moiety withtrimethylsilylbromide in a solvent such as DMF or acetonitrile and theresulting compound is converted to the desired prodrug 63-2, 63-3, 63-4using the methods of phosphonate ester and amidate formation describedbelow.

Scheme 63.2 describes the synthesis of a compound 63-9, a particularmember of the general class of compounds described by the structure63-2, 63-3, 63-4. Compound 63-1 is treated withdiethylphosphonomethyltrifluorosulphonate, 63-5, in pyridine to yieldthe ether 63-6. Compound 63-6 is treated with trimethylsilylbromide inacetonitrile to yield the free phosphonic acid 63-7. Compound 63-7 isthen treated with dicyclohexylcarbodiimide and phenol in DMF to yieldthe monophenol ester 63-8, which is then condensed with theisopropylester of alanine using aldrithiol and triphenylphosphine in DMFto yield the desired prodrug 63-9

Example 64 Preparation of Exemplary Compounds of the Present Invention

Synthetic sequences to examples of such phosphonates are described inScheme 64.1.

Rapamycin, a synthetic precursor of everolimus, is O-arylated as shownabove using an appropriate aryl bismuth reagent according to a proceduresuch as that reported in Bioorg. Med. Chem. Lett, (1995), 5, 1035.3-(Dimethyl-t-butylsilyloxy)bromobenzene is treated either withmagnesium in diethyl ether or with butyllithium in tetrahydrofuran, andthe resulting organometallic reagent is reacted with bismuth trichlorideto generate the triarybismuthine. After treating with 1-1.2 equivalentsof peracetic acid, the bismuth(V) reagent is then mixed with rapamycinand copper(II) acetate. The reaction is allowed to proceed for a day atroom temperature or, if necessary, at reflux, affording the desired3-(dimethyl-t-butylsilyloxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group, O-alkylation is achieved withdiethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired everolimus analog containing thediethylphosphonate. Silver ion-assisted reactions have been used tomediate O-alkylations on an immunosuppresive macrolide structurallysimilar to rapamycin: see J. Med. Chem., (1998), 41, 1764.

A phosphonate derivative of everolimus indolyl ether is prepared asdepicted in Scheme 64.2, in a similar manner to the previous examplewith the exception that the key triindolylbismuthine intermediate isobtained from 5-bromoindole following the procedure described in J. Org.Chem. (1998), 63, 6721.

Example 65 Preparation of Exemplary Compounds of the Present Invention

Synthetic sequences to examples of such phosphonates are described inScheme 65.1.

Sirolimus is O-arylated as shown above using an appropriate aryl bismuthreagent according to a procedure such as that reported in Bioorg. Med.Chem. Lett, (1995), 5, 1035. 3-(dimethyl-t-butylsilyloxy)bromobenzene istreated either with magnesium in diethyl ether or with butyllithium intetrahydrofuran, and the resulting organometallic reagent is reactedwith bismuth trichloride to generate the triarybismuthine. Aftertreating with 1-1.2 equivalents of peracetic acid, the bismuth(V)reagent is then mixed with sirolimus and copper(II) acetate. Thereaction is allowed to proceed for a day at room temperature or, ifnecessary, at reflux, affording the desired3-(dimethyl-t-butylsilyloxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group, O-alkylation is achieved withdiethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired sirolimus analog containing thediethylphosphonate. Silver ion-assisted reactions have been used tomediate O-alkylations on an immunosuppresive macrolide structurallysimilar to sirolimus: see J. Med. Chem., (1998), 41, 1764.

A phosphonate derivative of sirolimus indolyl ether is prepared asdepicted in Scheme 65.2, in a similar manner to the previous examplewith the exception that the key triindolylbismuthine intermediate isobtained from 5-bromoindole following the procedure described in J. Org.Chem. (1998), 63, 6721.

Example 66 Preparation of Exemplary Compounds of the Present Invention

Synthetic methodology towards compounds such as these is described in WO09/613,266, according to the general routes outlined in Schemes66.1-66.3.

The protected tyrosine derivative can be treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester. Subsequent selective hydrolysis of thecarboxylate ester using a source of hydroxide ion such as lithiumhydroxide in a solvent such as ethanol provides thephosphonate-containing reagent in a form suitable for use in thesynthesis of bortezomib analogs.

The protected tyrosine derivative can be treated in a solvent such asdimethylformamide or tetrahydrofuran with a base such as sodium hydride.When bubbling ceases, E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. This is thenheated with triethylphosphite in a solvent such as toluene (or otherArbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988) to generate the diethyl esterof the desired phosphonic acid. Subsequent selective hydrolysis of thecarboxylate ester using a source of hydroxide ion such as lithiumhydroxide in a solvent such as ethanol provides thephosphonate-containing reagent in a form suitable for use in thesynthesis of bortezomib analogs.

Example 67 Preparation of Exemplary Compounds of the Present Invention

Reduction of the dose and/or improvement of efficacy is achieved by theuse of pro-drugs of analogs of VX-148 which, upon cleavage inside thetarget cell, give rise to an agent with an increased intracellularhalf-life. Such compounds are described below.

Link includes 0-8 atoms; 2-6 is preferred

Compounds such as these can be made according to the general routesoutlined in Schemes 67.2, 67.4 and 67.5, with syntheses of suitablereagents depicted in Schemes 67.3 and 67.6.

A 3,5-difunctionalized nitrobenzene derivative provides a suitablestarting point for a reagent that contains a phosphonate moiety linkedto the phenyl ring at the desired position, ready for incorporation intothe fully-crafted VX-148 analog using methods developed for the parentcompound.

3-Hydroxy-5-nitro-benzoic acid is heated briefly in thionyl chloride togenerate the acid chloride. This is then condensed withO,N-dimethyl-hydroxylamine in the presence of a base such astriethylamine to produce the Weinreb amide which, upon reaction withmethyl lithium, gives the acetophenone derivative. This is then treatedwith a base such as potassium carbonate in a dipolar aprotic solventsuch as dimethylformamide, in the presence of an excess ofE-1,4-dibromobutene. The monobromide is isolated by chromatography andthen subjected to treatment with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, (1988)) to generate the desiredphosphonate diethyl ester. Thereafter, the carbonyl of the acetophenoneis reduced enantioselectively using an appropriate homochiraloxazaborolidine such as that described by Corey (J. Am. Chem. Soc.,(1987), 109, 5551), and the resulting alcohol is displaced by azideusing a method such as that described by Mitsunobu (Bull. Chem. Soc.Japan., (1971), 44, 3427). The azide is reduced to the amine underStaudinger conditions (Helv. Chim. Act., (1919), 2, 635) and protectedas the t-butyl carbonate. Finally, the desired aniline is generated bytin (II)-mediated reduction of the nitrobenzene.

Reagents suitable for use in the synthesis of phosphonate analogs aremade by routes analogous to that shown in Scheme 67.3, starting from2-hydroxy-5-nitro-benzoic acid.

An example of the synthesis of a suitable reagent for coupling reactionsas in U.S. Pat. No. 6,054,472 and U.S. Pat. No. 6,344,465 is illustratedin Scheme 67.6 below.

3-tert-Butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid(commercially available) is coupled with 2-aminoethylphosphonic aciddiethyl ester (commercially available) using standard reagents for theformation of a secondary amide such as dicyclohexylcarbodiimide (DCC)and hydroxybenztriazole (HOBT), in a solvent such as dimethylformamide.Subsequent reduction of the nitro group proceeds in a fashion similar tothat described in Scheme 67.3.

Example 68 Preparation of Exemplary Compounds of the Present Invention

Compounds such as these can be made according to the general routesoutlined in Schemes 68.1, 68.3 and 68.4, with syntheses of suitablereagents depicted in Schemes 68.2 and 68.5.

A 3,5-difunctionalized nitrobenzene derivative provides a suitablestarting point for a reagent that contains a phosphonate moiety linkedto the phenyl ring at the desired position, ready for incorporation intothe fully-crafted merimepodib analog using methods developed for theparent compound.

3-Hydroxy-5-nitro-benzoic acid is heated briefly in acidic methanol togenerate the methyl ester. This is then treated with a base such aspotassium carbonate in a dipolar aprotic solvent such asdimethylformamide, in the presence of an excess of E-1,4-dibromobutene.The monobromide is isolated by chromatography and then subjected totreatment with triethylphosphite in a solvent such as toluene (or otherArbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press (1988)) to generate the desiredphosphonate diethyl ester. Thereafter, the benzoate ester is saponifiedand reduced, and the resulting alcohol displaced by azide using a methodsuch as that described by Mitsunobu (Bull. Chem. Soc. Japan., (1971),44, 3427). The azide is reduced to the amine under Staudinger conditions(Helv. Chim. Act., (1919), 2, 635) and protected as the t-butylcarbonate. Finally, the desired aniline is generated by tin(II)-mediated reduction of the nitrobenzene.

Reagents suitable for use in the synthesis of phosphonate analogs ofType II may be made by routes analogous to that shown in Scheme 68.2,starting from 2-hydroxy-5-nitro-benzoic acid.

An example of the synthesis of a suitable reagent for coupling reactionsas in U.S. Pat. No. 6,054,472 and U.S. Pat. No. 6,344,465 is illustratedin Scheme 68.5 below.

3-Nitrobenzaldehyde reacts with a Grignard reagent to introduce a tetherbearing a protected alcohol and simultaneously to generate a benzylicalcohol, as shown. The alcohol is displaced by an azide in a mannersimilar to that described for Scheme 68.2. After deprotection, theliberated alcohol is alkylated with diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., (1986), 27, 1477) using a basesuch as magnesium tert-butoxide in a solvent such as tetrahydrofuran.Subsequent transformations of the azide and nitro groups proceed in afashion similar to that described in Scheme 68.2.

Example 69 Preparation of Exemplary Compounds of the Present Invention

Synthetic methodology towards compounds such as these is based onmethods described by Batt et al, Bioorg. Med. Chem. Lett., (1995), 5,1549. A typical general route is outlined in Scheme 69.1.

Examples of the synthesis of suitable phosphonate-containing analogs areshown below.

The initial Pfitzinger condensation is classically achieved in a singlestep using potassium hydroxide with acidic work-up, as shown.Alternatively, the initial aldol condensation may be performed usingdiethylamine in ethanol, and the quinoline ring may be formed is asecond step mediated by an acid such as hydrochloric acid in a solventsuch as 1,4-dioxane. Following removal of the benzyl protecting groupvia hydrogenation, the phenol can be treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., (1986), 27, 1477) is added, yielding thedesired phosphonate diester. The carboxylate is deprotected by treatmentwith lithium hydroxide in ethanol.

The synthesis is similar to that depicted in Scheme 69.2 except that,following deprotonation of the phenol, E-1,4-dibromobutene is added inexcess. After quenching the reaction with aqueous ammonium chloride andextracting the product with an organic solvent such as ethyl acetate,the mono-alkylated product is isolated by chromatography. The resultingbromide is heated with triethylphosphite in a solvent such as toluene togenerate the diethyl ester of the desired phosphonic acid, and thecarboxylic acid is deprotected as before.

Example 70 Preparation of Exemplary Compounds of the Present Invention

The structures of Dexamethasone 70-1 (U.S. Pat. No. 3,007,923) and thephosphonate esters 70-4 are shown in Scheme 70.1, in which thesubstituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. The compounds 70-4incorporate a phosphonate moiety (R¹O)₂P(O) connected to the nucleus bymeans of a variable linking group, designated as “link” in the attachedstructures.

Schemes 70.2-70.12 illustrate the syntheses of the phosphonate compoundsof this invention and of the intermediate compounds useful for theirsynthesis.

Protection of Reactive Substituents.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990. The protection anddeprotection of steroidal ketones and alcohols is described in OrganicReactions in Steroid Chemistry, Vol. 1, J. Fried and J. A. Edwards, vanNostrand Reinhold, (1972), p. 375ff. Reactive substituents which may beprotected are shown in the accompanying schemes as, for example, [OH],[O], etc. For example, Scheme 70.1 depicts a protection-deprotectionsequence in which the steroid side-chain is protected as abis-methylenedioxy (BMD) moiety. In this sequence, Dexamethasone 70-1 isreacted with paraformaldehyde and an acid catalyst such as hydrochloricacid, as described in Protective Groups in Organic Synthesis, by T. W.Greene and P. G. M. Wuts, Wiley, Second Edition (1990), p. 223, to yieldthe BMD derivative 70-2. The phosphonate moiety is then introduced,using the procedures described below, to produce the phosphonate ester70-3. The BMD moiety is then hydrolyzed, for example by treatment with50% aqueous acetic acid, as described in Protective Groups in OrganicSynthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition(1990), p. 223, to afford the triol 70-4.

Preparation of the Phosphonate Esters 70-7, 70-14, 70-18, 70-20, 70-120,70-22, and 70-27.

Schemes 70.2-70.6 depicts the preparation of phosphonates in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain. In this procedure, the BMD-protected derivative70-2 is reacted with an amine or hydroxylamine 70-5, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133. and in J. Mass. Spectrom., (1995), 30, 497. TheBMD-protected side-chain compound 70-6 is then converted, as describedin Scheme 70.1, into the triol 70-7.

Schemes 70.2-70.6 also illustrates the preparation of hydroxylamineethers incorporating a phosphonate group. In this procedure, aphosphonate 70-8, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine 70-9(Aldrich) to produce the ether 70-10. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether 70-11.

Scheme 70.3 illustrates the preparation of phosphonates 70-14 in whichthe phosphonate is attached by means of an iminoxy group. In thisprocedure, the substrate 70-2 is reacted with a dialkyl phosphonomethylhydroxylamine 70-12, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime 70-13 which isdeprotected to afford the triol 70-14. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants. Using the above procedures, butemploying, in place of the hydroxylamine ether 70-12, different oximeethers 70-5, the corresponding products 70-7 are obtained.

Scheme 70.4 illustrates the preparation of compounds 70-18, 70-20, and70-180 in which the phosphonate group is attached by means of a pyridylmethoxy group. In this procedure, the dienone 70-2 is reacted, asdescribed above, with O-(3-bromo-5-pyridylmethyl)hydroxylamine 70-15,prepared as described above from 3-bromo-5-bromomethylpyridine (WO95/28400), to give, after deprotection of the side-chain, the oxime70-16. The product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite 70-17 to afford the phosphonate70-18. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 35, 1371, (1992). The reaction is performed in an inertsolvent such as toluene, in the presence of a base such as triethylamineand a catalytic amount of tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound 70-16 is coupled with a dialkylvinylphosphonate 70-19 (Aldrich) to afford the phosphonate 70-20. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, (2001), p. 503ff and in Ace. Chem. Res., 12,146, (1979). The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 70-20 isreduced, for example by reaction with diimide, to produce the saturatedanalog 70-120. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, (1989), p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromopyridyloxy reagent 70-15, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds 70-18, 70-20 and70-120 are obtained.

Scheme 70.5 depicts the preparation of phosphonates 70-22 in which thephosphonate is attached by means of an imino group. In this procedure,the substrate 70-2 is reacted with a dialkyl 2-aminophenyl phosphonate70-21, (Syn., (1999), 1368) to give, after deprotection, the imineproduct 70-22. The reaction is conducted in a hydrocarbon solvent suchas toluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 2-aminophenylphosphonate 70-21 different amino-substituted aryl or heteroarylphosphonates, products analogous to 70-22 are obtained.

Scheme 70.6 illustrates the preparation of phosphonates 70-27 in whichthe phosphonate is attached by means of an oximino group and an amidelinkage. In this procedure, the dienone 70-2 is reacted withO-(2-carboxyethyl)hydroxylamine 70-23 (J. Med. Chem., 1990, 33, 1423) toyield the oxime 70-24. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch., (1976), 7,795; the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then reacted with a dialkyl aminomethyl phosphonate 70-25 (AsInEx),to yield the amide oxime 70-26. The preparation of amides fromcarboxylic acids and derivatives is described, for example, in OrganicFunctional Group Preparations, by S. R. Sandler and W. Karo, AcademicPress, (1968), p. 274, and Comprehensive Organic Transformations, by R.C. Larock, VCH, (1989), p. 972ff. The carboxylic acid is reacted withthe amine in the presence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide.

The amide product 70-26 is then converted, as described in Scheme 70.1,into the triol 70-27.

Using the above procedures, but employing, in place of the hydroxylamine70-25, different carboxy-substituted hydroxylamines, and/or differentamino-substituted phosphonates, the products analogous to 70-27 areobtained.

Preparation of the Phosphonate Esters 70-33, 70-35, 70-40, 70-41, 70-47,70-147, and 70-48.

Schemes 70.7-70.9 illustrates the preparation of the phosphonate estersin which the phosphonate group is attached to the 1′ or 2′ position ofthe pyrazole ring, by means of an aromatic or heteroaromatic group, aheteroatom and a variable carbon chain. In this procedure, theBMD-protected dienone 70-2 is reduced to afford the 1,2-dihydro product70-74. The catalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (1) chloride, for example as describedin J. Med. Chem., (2001), 44, 602. The product is then reacted withethyl formate and a base such as sodium hydride, in an inert solventsuch as toluene or dimethylformamide, as described in J. Am. Chem. Soc.,1964, 86, 1520, to afford the 2-formyl product 70-28. This compound isthen reacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine 70-29,in which the substituent X is either a phosphonate group or a groupwhich is subsequently transformed into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxyl and the like. The reaction yields the isomeric 2′- and 1′-arylpyrazoles 70-30 and 70-31. The pyrazole-forming reaction is performedbetween equimolar amounts of the reactants in an acidic solvent such asacetic acid, as described in J. Am. Chem. Soc., 1964, 86, 1520. Thepyrazoles 70-30 and 70-31 are then transformed, for example by theprocedures described in Schemes 70.8-70.9, via the BMD-protectedintermediates 70-34 and 70-32, into the phosphonates 70-35 and 70-33.

Scheme 70.8 illustrates the preparation of phosphonates and in which thephosphonate is attached by means of a phenyl ring and an alkoxy or anacetylenic linkage. In this procedure, the ketoaldehyde 70-28 isreacted, as described above, with 3-hydroxyphenylhydrazine 70-36(Japanese patent JP 03011081) to give the pyrazoles 70-70 and 70-37. The2′-substituted isomer 70-70 is then reacted in dichloromethane solutionat ambient temperature with one molar equivalent oftrifluoromethylsulfonyl chloride and dimethylaminopyridine, to yield thetriflate 70-39. The product is then reacted in toluene solution with adialkyl propynyl phosphonate 70-71 (Syn (1999), 2027), triethylamine anda catalytic amount of tetrakis(triphenylphosphine)palladium (0), to givethe acetylenic product 70-73. The palladium-catalyzed coupling reactionof aryl triflates with terminal acetylenes is described in WO 0230930.The BMD protecting group is then removed to yield the triol 70-41.

Alternatively, the 1′-substituted pyrazole 70-37 is reacted, in aMitsonobu reaction, with a dialkyl 2-hydroxyethyl phosphonate 70-72(Epsilon) to afford the ether 70-38. The preparation of aromatic ethersby means of the Mitsonobu reaction is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, (2001), p. 153-4 and in Org. React., (1992), 42, 335.The phenol and the alcohol component are reacted together in an aproticsolvent such as, for example, tetrahydrofuran, in the presence of adialkyl azodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,(1992), 42, 335-656. The product 70-38 is then deprotected to give thetriol 70-40.

Using the above procedures, but employing different acetylenic orhydroxyl-substituted phosphonates, the products analogous to 70-41 and70-40 are obtained. The functionalization procedures are interchangeablebetween the pyrazole substrates 70-70 and 70-37.

Scheme 70.9 illustrates the preparation of the phosphonates in which thephosphonate group is attached by means of a benzyl group or a benzylgroup and a saturated or unsaturated carbon chain. In this procedure,the ketoaldehyde 70-28 is reacted, as described above, with3-bromobenzyl hydrazine 70-75 (U.S. Pat. No. 4,370,339) to produce thepyrazoles 70-42 and 70-43. The 1′-substituted isomer 70-42 is coupled,in the presence of a palladium catalyst, with a dialkyl vinylphosphonate70-76 (Aldrich) to give the phosphonate 70-46. The product is thendeprotected to afford the triol 70-47. Optionally, the styrenoid doublebond present in the product 70-47 is reduced, as described above, toproduce the saturated analog 70-147.

Alternatively, the 2′-substituted pyrazole 70-43 is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate 70-44 which is deprotected to give the triol 70-48. Thepreparation of arylphosphonates by means of a coupling reaction betweenaryl bromides and dialkyl phosphites is described in J. Med. Chem., 35,1371, (1992). This reaction is performed in an inert solvent such astoluene, in the presence of a base such as triethylamine andtetrakis(triphenylphosphine)palladium(0).

Using the above procedures, but employing, in place of the bromobenzylreagent 70-75, different bromo-substituted aralkyl, aryl or heteroarylalkoxy hydrazines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 70-47, 70-147 and 70-48 areobtained.

Schemes 70.10-70.12 depicts the preparation of the phosphonate esters inwhich the phosphonate group is attached by means of a variable carbonlinkage. In this procedure, the ketoaldehyde 70-28 is reacted withhydrazine, to afford the pyrazole derivative 70-49. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound 70-77, in which R² and X are as defined above, to yield thealkylation products 70-50 and 70-51. The alkylation of substitutedpyrazoles is described, for example, in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, (1992), p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts 70-50 and 70-51 are, except in cases where X isdialkylphosphono, converted into the phosphonates 70-52 and 70-53, usingthe procedures described herein, and deprotection then affords thetriols 70-54 and 70-55.

As shown in Scheme 70.11, the pyrazole 70-49 is reacted, as describedabove, with one molar equivalent of a dialkyl bromoacetonyl phosphonate70-78 (Tet., 1978, 34, 649) to give the alkylated pyrazoles 70-82 and70-83. Deprotection then yields the triols 70-84 and 70-85.

As shown in Scheme 70.12, the pyrazole 70-49 is reacted, as describedabove, with 1,4-bis(bromomethyl)benzene 70-86 to give the pyrazoles70-87 and 70-56. The products are subjected to an Arbuzov reaction, inwhich the bromomethyl substituent is converted into the dialkylphosphonomethyl substituent, by reaction with a trialkyl phosphite at120°, to prepare, after deprotection of the side chain, the phosphonates70-57 and 70-58. The Arbuzov reaction is described in Handb.Organophosphorus Chem., (1992), 115-72. In the procedure, the substrateis heated at from 60° to about 160° with a five to fifty-fold molarexcess of the trialkyl phosphite.

Using the above procedures, but employing, in place of the dibromide70-86, different dibromides, the products analogous to 70-57 and 70-58are obtained.

Example 72 Preparation of Exemplary Compounds of the Present Invention

Synthetic methodology towards compounds such as these is described byWestwood et al, J. Med. Chem., (1996), 39, 4608-4621, according to thegeneral routes outlined in Scheme 72.1.

Examples of the synthesis of suitable phosphonate-containing anilinesare shown below.

Example 73 Preparation of Exemplary Compounds of the Present Invention

Compounds of the invention can be prepared as generally described byWestwood et al, J. Med. Chem., (1996), 39, 4608-4621, according to thegeneral route outlined in Scheme 73.1.

Examples of the synthesis of suitable phosphonate-containing anilinesare shown below.

3-Nitrophenol is alkylated with E-1,4-dibromobutene and the resultingmonobromide is heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., Synthesisof carbon-phosphorus bonds, CRC press, 1988) to generate the diethylester of the desired phosphonic acid. Finally, the desired aniline isgenerated by tin (II)-mediated reduction of the nitrobenzene.

The methyl ester of 3-nitro-4-trifluoromethylbenzoic acid is treatedwith tin (II) chloride to produce the aniline. The 3-iodobenzoic acid isgenerated by diazotization and treatment with potassium iodide. Adiethylphosphonate ester is attached via an acetylene linker usingpalladium catalysis, and after saponification of the benzoate ester,Curtius rearrangement of the acyl azide reveals an aniline suitable forincorporation into the synthesis of teriflunomide analogs.

Example 74 Preparation of Exemplary Compounds of the Present Invention

The starting carboxylic acid, synthesized according to J. Am. Chem.Soc., (1948), 70, 1922-1926, is treated in a solvent such as DMF or NMPwith a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,2-aminoethylphosphonic acid diethyl ester (commercially available) isadded. After consumption of the activated species is observed thesolvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

The starting carboxylic acid is treated in a solvent such as DMF or NMPwith a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., (1982), 25, 960-964 and J. Med. Chem.,(1984), 27, 600-604). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added. After consumption of the activated speciesis observed the solvent is removed in vacuo and the intermediate isisolated by chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated by chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

The starting carboxylic acid is treated in a solvent such as DMF or NMPwith a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604.).When the activation is complete,(L)-2-amino-6-(diethylphosphonato)-hexanoic acid is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the product is isolated by chromatography. Alternatively,the product can be isolated through precipitation from the reactionsolution with an organic solvent like diethyl ether or the like.

The starting carboxylic acid is treated in a solvent such as DMF or NMPwith a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., (1982), 25, 960-964 and J. Med. Chem., (1984), 27, 600-604). Whenthe activation is complete, 4-amino-4-(diethylphosphonato)-butyric acidtert butylester (J. Am. Chem. Soc., (1995), 117, 10879-10888) is added.After consumption of the activated species is observed the solvent isremoved in vacuo and the intermediate is isolated by chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated by chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventlike diethyl ether or the like.

Example 75 Preparation of Exemplary Compounds of the Present Invention

The phosphorus containing merimepodib analog 75-2 is synthesized fromparent compounds by alkylation. Merimepodib 75-1 is obtained by theprocedure as described in U.S. Pat. No. 6,054,472 and U.S. Pat. No.6,344,465. Schemes 75.1-75.2 shows the procedure for the synthesis of75-2 and 75-4. Methoxy group of merimepodib 75-1 is demethylated tophenolic OH using a suitable reagent, such as boron tribromide. Thephosphonate moiety is introduced to the phenolic OH in a suitableaprotic solvent such as, DMF and is then treated with the phosphonatereagent 75-40, 75-41, bearing a leaving group, for example, bromine,mesyl, tosyl, or trifluoromethanesulfonyl, in the presence of a suitableorganic or inorganic base.

For example, a solution of 75-1 in dichloromethane is treated with borontribromide to obtain the demethylated compound 75-3. Compound 75-3 isthen treated with cesium carbonate and one equivalent of(trifluoromethanesulfonyloxy)methylphosphonic acid diethyl ester 75-41to give merimepodib-phosphonate 75-4 in which the linkage is a methylenegroup as shown in Scheme 75.2. Using the above procedure but employingdifferent phosphonate reagents 75-40 the corresponding products 75-2bearing different linking group can be obtained.

Synthesis of merimepodib analogs 75-2, 75-12 and 75-13 is shown inSchemes 75.3-75.4. The imidazole containing intermediate 75-7 issynthesized from an aldehyde 75-6 by the procedure of Shih inTetrahedron Lett. (1993), 34, 595. Compound 75-6 is prepared by atwo-step procedure described in U.S. Pat. No. 5,807,876, U.S. Pat. No.6,054,472, and U.S. Pat. No. 6,344,465. The imidazole is protected usingsuitable reagent, for example 2-(trimethylsilyl)ethyoxymethyl (SEM)chloride, and the compound 75-8 is converted to 75-10 by the similarprocedure described for the synthesis of 75-1 in U.S. Pat. No. 6,054,472and U.S. Pat. No. 6,344,465. After the protecting group on the imidazoleof 75-10 is removed, the phosphonate containing moiety is introduced tothe imidazole as shown in Schemes 75.4.

For example, compound 75-10 is treated with tetrabutylammonium fluoridein THF in reflux condition and the resulting 75-11 is alkylated with75-41, 75-42 using sodium hydride as a base to obtain two isomers 75-12and 75-13, which are separated by chromatography.

Schemes 75.5-75.6 shows the preparation of merimepodib analog 75-17.Tetrasubstituted benzene derivatives are obtained by literatureprocedures (Ichikawa and Ichibagase Yakugaku Zasshi (1963), 83, 103;Norio, A. et al. Tetrahedron Lett. (1992), 33(37), 5403). After thephenolic OH is protected with a suitable protecting group, for examplebenzyl group, the compound 75-16 is synthesized by the same procedure ofthe synthesis of 75-1 as described in U.S. Pat. No. 6,054,472, and U.S.Pat. No. 6,344,465. After the protecting group is removed, thephosphonate containing moiety is introduced to the phenolic OH using thephosphonate reagent 75-45, bearing a suitable leaving group.

For example, a solution of 75-18, which is obtained by the procedure ofNorio et al. (Tetrahedron Lett. (1992), 33(37), 5403), is treated withsodium hydride and one equivalent of benzyl bromide in DMF to get 75-19.Compound 75-19 is converted to 75-20 by a series of steps reported inU.S. Pat. No. 6,054,472, and U.S. Pat. No. 6,344,465 for the synthesisof 75-1 from 75-6. After the benzyl protecting group of 75-20 is removedby catalytic hydrogenation, a phosphonate bearing moiety is attached byalkylation of the resulting phenol in DMF using sodium hydride and oneequivalent of (trifluoromethanesulfonyloxy)methylphosphonic acid diethylester 75-42 to give 75-21.

Synthesis of merimepodib analog 75-26 is shown in Schemes 75.7-75.8.Compound 75-22, an intermediate in the synthesis of 75-1, is treatedwith carbonyldiimidazole or triphosgene followed by the compound 75-23,which has an handle to attach phosphonate moiety. Compound 75-23 bearingan extra substituent is synthesized from the tri substituted phenol witha cyano and a nitro groups, which is either commercially available or byliterature procedures (Zolfigol, M. A. et. al. Indian J. Chem. Sect. B(2001), 40, 1191; De Jongh, R. O. et al. Recl. Trav. Chim. Pays-Bas(1968), 87, 1327). The resulting 75-24 is converted to 75-25 using theprocedure described in U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465 for the synthesis of 75-1. The phosphonate moiety of 75-26 isattached after deprotection of the benzyl group of 75-25.

For example, the bromine substituent of compound 75-27 is substitutedwith cyano group by the procedure of De Jongh, R. O. et al. (Recl. Trav.Chim. Pays-Bas (1968), 87, 1327) and the methoxy group is converted tobenzyloxy group as a protecting group, which affords compound 75-28.After selective reduction of cyano to aminomethyl group by borane, theamino group is protected with Boc group and then the reduction of thenitro group using tin (II) chloride generates compound 75-29. Thissubstituted aniline 75-29 is then treated with a reaction mixture of thecompound 75-22 and carbonyldiimidazole, as described for the synthesisof 75-1 in U.S. Pat. No. 6,054,472, and U.S. Pat. No. 6,344,465, to formthe urea 75-30. Compound 75-30 is easily converted to 75-31, analog of75-1 bearing benzyloxy group. Deprotection of the benzyl group usingcatalytic hydrogenation followed by attachment of a phosphonate moietyusing 75-41, 75-42 in the presence of cesium carbonate produces 75-32.

Example 76 Preparation of Exemplary Compounds of the Present InventionPreparation of Phosphonate Prodrugs of Tamoxifen and Toremifene Citrate

A number of analogs of tamoxifen have been prepared and tested. A highdegree of flexibility is observed at the aminoethyl portion of thecompound toward substitution (Meegan et al. Anti-Cancer Drug Design,(2001), 16, 57). Based on the available SAR, this position is chosen asone handle for attachment of the prodrug moiety. A large number ofanalogs of tamoxifen have been reported, many having favorable profiles.For a review on a number of tamoxifen analogs, see Meegan, M. J., Lloyd,D. G., Current Medicinal Chemistry, (2003), 10, 181. Considering thatthese analogs are similar to tamoxifen, the prodrug approach on the samesite as tamoxifen can be applied to them. A number of additional siteson the tamoxifen core are available for attachment of the prodrug group.Considering the scale up methods that are well established fortamoxifen, attachment of prodrug through the amino ethanol group on theB ring is one option. The original synthesis of tamoxifen (Harper etal., GB1064629 and Harper et al., GB1013907) has been modified recently(Smyth, T. P., Corby, B. W., Organic Process Research & Development,(1997), 1, 264). This new method was developed for large scalepreparation. Additionally, installation of the amino ethyl groupattached to the B ring is performed late in the synthesis which isadvantageous for one prodrug synthesis.

Synthesis of compounds such as phosphonate 1 (of Scheme 76.1) areillustrated above. Compounds 1.1 and 1.2 (of Scheme 76.1) are condensedusing trifluoroacetic anhydride as described in Smyth et al., OrganicProcess Research & Development, (1997), 1, 264. Replacement of thehalogen with amino-linker-phosphonate provides compound 1.4 (in Scheme76.1). A final Grignard reaction to introduce the last aromatic group,followed by dehydration in acidic medium provides compound 1 (of Scheme76.1). The order of the last two steps can be switched. First, aGrignard reaction can be performed to install the tetrasubstitutedolefin followed by displacement of halogen (McCague R., J. Chem. Res.,1986, 0771). The final product is a mixture of cis and trans isomerswhich are separated by crystallization. Also, further diversity onto thearomatic A ring is incorporated by choice of substitutions attached tothe arylbromide that is used in the Grignard reaction.

Specifically, preparation of compound 1.3 (of Scheme 76.2) is completedas described in literature. Alkylation with amino ethyl phosphonate isperformed to replace the chloride in 1.3 to form 1.4 (Scheme 76.2). AGrignard reaction with bromobenzene gives compound 1.5 (of Scheme 76.2)which is dehydrated under acidic conditions to provide compound 1 (ofScheme 76.2) as the HCl salt. The citrate salt is another usefulcompound. Other salts can also be generated.

Syntheses of a number of analogs of toremifene are described in detailin U.S. Pat. No. 4,696,949. Synthesis of prodrugs of toremifene is shownabove in Scheme 76.3. The prodrug is installed early in the synthesis.It is possible to protect the 4-hydroxy benzophenone initially andremove the protecting group near the end of the synthetic sequence. Inthat case, the prodrug group is installed near the end of the synthesis.The preparation shown in Scheme 76.3 utilizes 4-hydroxy benzophenone asthe starting materials. A two carbon linker is attached and subsequentlyactivated toward synthesis of compound 2.3 (of Scheme 76.3).Introduction of the aminophosphonate 2.1.1 (of Scheme 76.3) at thisstage completes the left half of the molecule. Addition ofcinnamaldehyde to lithium aluminium hydride followed by the benzophenone2.4 yields diol 2.5 (both of Scheme 76.3). Dehydration of 2.5 andconversion of the 4-OH to chloride is performed by addition of thionylchloride to provide compound 2.6 (of Scheme 76.3). Final product 2(Scheme 76.3) is prepared by formation of the desired salt.

Specifically, 4-hydroxy benzophenone is reacted with 1-mesyl ethane diolto yield 2.2 (of Scheme 76.4) in CH₂Cl₂. Activation of alcohol 2.2(Scheme 76.4) to mesylate 2.3 (Scheme 76.4) is performed using mesylchloride in CH₂Cl₂ using TEA as a scavenger. Alkylation of mesylate 2.3with the N-methyl amino ethyl phosphonate 2.1.1 (of Scheme 76.4) in EtOHat 80° C. proceeds well to provide compound 2.4 (Scheme 76.4). Additionof 2.4 (I equivalent) to a mixture of cinnamaldehyde (1 equivalent) andlithium aluminum hydride (0.55 equivalent) in THF yields compound 2.5(of Scheme 76.4) after 30 minutes of stirring at room temperature.Dehydration of 2.5 (Scheme 76.4) using thionyl chloride in toluene iscomplete after 3 hours at 80° C. to provide compound 2.6 (Scheme 76.4).A variety of salts can be prepared subsequently. The citrate salt oftoremifene is one exemplary compound. Further modification of thephosphonate prodrug can be performed to the phosphonate diester,bisamidate, or monoamidate as illustrated above.

Example 77 Preparation of Exemplary Compounds of the Present InventionPreparation of Phosphonate Prodrugs of Raloxifene Hydrochloride

Many structural modifications of raloxifene have been investigated andthe SAR of this group of drugs is well established. In brief, thehydroxyl substituents of aryl rings of raloxifene are predictablycritical to the potent activity of the compound. The C-6 OH ispositioned to bind to the ER residue pair Arg 394/Glu 343 in the sameway as the 3-OH of estradiol. Also, the 4′-OH, which mimics the 17β-OHof estradiol, binds with the His 524 as demonstrated by crystalstructure studies (Anzo, et al., J. Natl. Cancer Inst., (1996), 88,123). The amine of the piperidine ring is also important in binding tothe aspartate 351 of the estrgen receptor. This amine also plays a rolein tissue specificity. However, a number of N,N-dialkyl analogs ofraloxifene show equipotent activity to the parent compound. Therefore,substitution of the prodrug group at that terminus of the compound is apreferred embodiment of this work.

Three types of substitutions are set forth herein. Two are variations ofattachement of prodrug to the tertiary amine region (Scheme 77.1).Another attachment site on the raloxifene is the carbonyl position.Considering this carbonyl moiety can be easily substituted with a simpleoxygen, this position can be used as a potential handle for thephosphonate prodrugs (Palkowitz, et al., J. Med. Chem., (1997), 40, 10,1407).

The first phosphonate prodrug is prepared following the general Schemes77.2-77.3. An appropriately protected diol is attached on to thephenolic position of 4-hydroxyl benzoic acid methyl ester by Williamsonether synthesis methods. Removal of the protecting group generatedcompound 77-5. Turning the hydroxyl group into an appropriate leavinggroup, such as mesyl, bromide of trifluoromethylsulfonyl, followed byaddition of amino phosphonate prodrug moiety gives compound 77-6, 77-50.Releasing the methyl ester, followed by activation of the acid byformation of the acid chloride proceeds as reported in literature(Jones, et al. J. Med. Chem., 1984, 27, 1057). Friedal-Crafts aroylationwith compound 77-7, 77-33, 77-25 which is the product of a rearrangement(Kost et al., Zh. Org. Khim, 1970, 6, 1503), (Jones, C. D., EP 0062503)goes smoothly to provide the protected desired compound. Finaldeprotection provides compound 77-9. Different salts can be prepared toassist the solubility of the final compound.

A particular example of the general route above is shown in Scheme 77.3.Compound 77-4 is alkylated with the TMS protected diol 77-23 using K₂CO₃in DMF. Removal of the silyl protecting group proceeds cleanly with TFAto provide precursor 77-5. Activation of 77-5 by formation of themesylate using MsCl and TEA in CH₂Cl₂, followed by addition of the aminoethyl phosphonate 77-22, 77-32 proceeds well to generate amine 77-6,77-50. Removal of the methyl ester protecting group of 77-6, 77-50followed by one-pot two step reactions of Friedal-Craftsaroylation-deprotection using thioethanol proceeds very well to generateHCl salt of the final compound 77-10, 77-35.

Generation of the piperazyl phosphonate prodrug is performed the sameway as for compound 77-10, 77-35. Synthesis of 77-24, 77-40 proceedsusing a mono protected piperazine and the 2-hydroxyethyl phosphonate.Subsequent steps in the synthesis are as described in Schemes 77.2-77.3.Specifically, addition of 77-24, 77-40 to 77-5 in CH₂Cl₂ using TEA as ascavenger gives 77-12, 77-42. Deprotection of the methyl ester,activation of the acid with thionyl chloride and the Friedal-Craftsaroylation proceed as before. Compound 77-15, 77-16 is generated by insitu deprotection of the methyl ethers using triethylsilane. Convertingthe final product into a bis-HCl salt improves solubility.

Generation of phosphonate prodrug 77-18, 77-19 is accomplished fromcommercial Raloxifene Hydrochloride. A reductive amination with anaminophosphonate generates the desired product. The reaction is carriedout using 77-15, 77-16 equivalents of sodium cyanoborohydride in CH₂Cl₂.The two enantiomers generated are separated by chiral chromatography.

Example 78 Preparation of Exemplary Compounds of the Present InventionPreparation of Phosphonate Prodrugs of Mycophenolate Mofetil

Three regions of mycophenolate mofetil are utilized for the attachmentof the phosphonate prodrug onto mycophenolic acid as demonstrated bycompounds 78-1 to 78-4 (Scheme 78.1). Also, the carboxylic acid isreplaced with a phosphonic acid which is part of the prodrug moiety asin compound 78-3.

The morpholino ethyl moiety which serves as prodrug to improvebioavailability is replaced with the phosphonate prodrug handle as shownin Schemes 78.2-78.3. Mycophenolic acid is commercially available, e.g.,from Sigma Chemical Company, St. Louis, Mo. Activation of the carboxylicacid 78-5 in the presence of the free phenol followed by addition of analcohol carrying the phosphonate group results in the formation of thedesired product (U.S. Pat. No. 4,786,637). Specifically, mycophenolicacid 78-5 is dissolved in dichloromethane. Thionyl chloride is addedfollowed by a catalytic amount of DMF. The reaction mixture is stirredat room temperature for 3 hours, after which the volatile components areremoved under vacuum. The phosphonate-alcohol is dissolved indichloromethane and chilled to 4° C. on an ice bath. The mycophenolicacid chloride 78-7 is dissolved in dichloromethane and added to thechilled solution. After stirring for 90 minutes at 4° C., the reactionmixture is washed with water and then with aqueous sodium bicarbonate.The organic solution is dried and evaporated to yield the phosphonateprodrug 78-6, 78-8.

The C-4 phenol position provides a reactive handle for further analogs(Schemes 78.4-78.5). Once the carboxylic acid is blocked by morpholinoethyl, such as in compound 78-9, or a phosphonate prodrug as in compound78-6, 78-8, the phenol is alkylated under basic conditions. Bases suchas pyridine, potassium carbonate, or triethylamine are utilized. Leavinggroups such as trifluoromethylsulfonate, mesylate, bromide, or iodideare attached to the phosphonate prodrug subunit and reacted in thepresence of base with compound 78-9. Compound 78-2, 78-45 can either beused directly, or in the form of a salt. Among the number of salts thatcan be prepared, chloride and bisulfate salts are of particularinterest.

Preparation of compound 78-10, 78-11 is outlined in more detail inScheme 78.5. Compound 78-7 is prepared as described in Scheme 78.3. Asolution of morpholino ethanol in dichloromethane is cooled to 4° C. Themycophenolic acid chloride 78-7 is dissolved in dichloromethane andadded to the cooled solution. Stirring this solution for 90 minutesgives compound 78-9. The reaction mixture is washed with water and driedwith sodium sulfate. Removal of the solvent provides compound 78-9.Alkylation at the phenolic position of 78-9 is achieved by suspendingthe compound in pyridine. Triflate 78-30 is added to the solution andthe mixture is stirred at room temperature for 90 minutes. The reactionmixture is poured into water and the product is extracted with ethylacetate. Removal of the organic layer provides compound 78-2, 78-45.Hydrochloride salt of 78-2, 78-45 is also prepared. Compound 78-2, 78-45is dissolved in isopropanol and the solution is added to a mixture ofhydrogen chloride in isopropanol. The hydrochloride salt 78-10, 78-11 iscollected by filtration and dried under vacuum.

The carboxylic acid of mycophenolic acid is replaced with a phosphonicacid which serves as the prodrug handle as well. In order to remove thecarboxylic acid containing side chain, the acid chloride 78-7 isconverted to ester 78-13, 78-33. Protection of the phenol with a silylgroup, followed by dihydroxylation and cleavage of the diol generatesaldehyde 78-15, 78-19 (Pankiewicz, et al., J. Med. Chem., (2002), 45,703), (Patterson et al., U.S. Pat. No. 5,444,072) (Schemes 78.6-78.7). Awittig reaction with ylide 78-50, 78-31 carrying an appropriatelyprotected phosphonate provides the desired compound 78-16, 78-20. Finaldeprotection yields compound 78-17.

Mycophenolate ester 78-13, 78-33 is prepared by stirring the acidchloride 78-7 with MeOH. Then, the phenol position of mycophenolateester is protected by a silyl group such as TBS to provide compound78-14, 78-18. Once the phenol position is protected, dihydroxylationusing osmium tetraoxide followed by periodinate cleavage providesaldehyde 78-15, 78-19. Aldehyde 78-15, 78-19 and excess of the ylide78-50, 78-31 are heated in benzene at reflux for 24 hours. The reactionmixture is concentrated and the residue is purified by columnchromatography to provide olefin 78-16, 78-20 (Pankiewics et al., J.Med. Chem., (2002), 45, 703). A final deprotection using HF-pyridineyields the final product 78-17.

Another attachment point of the compound is unmasked after demethylationof mycophenolate ester 78-9 (Schemes 78.8-78.9). For this purpose, 4-OHis masked with a protecting group such as a silyl group. Once the 6-MeOis demethylated and alkylated, the protecting group at position 4 isremoved to reveal the final product. The morphonyl ethanol group isinstalled early and carried through the alkylation steps. A differentgroup serving the role of the protecting group is installed initiallyand removed later. In that case, the last step is the formation of themorpholinoethyl ester prodrug.

Synthesis of compound 78-4 is shown in Scheme 78.9. Phenol 78-9 isprotected with TBS group in CH₂Cl₂ using imidazole as base.Demethylation is performed using thiolate nucleophiles to generatecompound 78-26, 78-22. A variety of other methods are also available inliterature as described in protective groups in organic synthesis byGreene and Wuts. Alklation of the 6-OH using a triflate of thephosphonate prodrug proceeds well using K₂CO₃ or TEA. Final deprotectionto remove the TBS group provides product 78-27, 78-24.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described in the following section.

Example 79 Preparation of Exemplary Compounds of the Present Invention

Derivatization at the C-21 hydroxy group is accomplished throughalkylation of dexamethasone 79-1 with the appropriate phosphonate,furnishing analogs of the type 79-2. (Scheme 79.1)

After sodium hydride extraction of the primary hydroxy proton in 79-1,diethyl phosphonate triflate is added to afford ether 79-3. (Scheme79.2)

Phosphonate appendages linked to the C-11 hydroxy group are attainedfrom utilizing protecting groups on dexamethasone 79-1. (Scheme 79.3)Following protection of the primary hydroxy group, protectedintermediate 79-4 is alkylated at the more exposed C-11 hydroxy site.Final deprotection provides the desired product 79-6.

Dexamethasone 79-1 is protected as its silyl ether using the standardTBSCl and imidazole conditions. (J. Am. Chem. Soc. 1972, 94, 6190)(Scheme 79.4) After alkylating with the diethyl phosphonate triflate,the resulting intermediate 79-8 is treated with TBAF to give the diol79-9.

Synthesis of C-21 phosphonate analogs of the type 79-12 is shown inScheme 79.5. Protection this time of dexamehtasone 79-1 at the two lesshindered sites furnishes alcohol 79-10, which is alkylated at the onlyexposed hydroxy group with the appropriate phosphonate. Removal of theprotecting groups completes the construction of analog 79-12.

Again dexamethasone 79-1 is protected as its TBS ether; however, harsherconditions are used for bis-protection. (Scheme 79.6) After alkylatingwith the diethyl phosphonate triflate, the resulting intermediate 79-14is treated with TBAF to give the desired phosphonate 79-15.

Example 81 Preparation of Exemplary Compounds of the Present InventionExperimental Results for Pro-Drugs of Phosphonate-Containing PNPInhibitors

The diacid (100 mg, 0.304 mmol), amino acid (100 mg, 0.651 mmol), phenol(145 mg, 1.54 mmol), and triethylamine (510 μL, 3.66 mmol) weredissolved in pyridine (5 mL). The mixture was heated to 60° C. for 5minutes. To this reaction mixture was added a solution oftriphenylphosphine (560 mg, 2.14 mmol) and Aldrithiol(2) (470 mg, 2.13mmol) dissolved in pyridine (5 mL). The reaction was then heated at 60°C. for 12 hours. The reaction mixture was diluted in EtOAc, washed withH₂O, sat'd NaHCO₃(aq), and brine. The organic layer was dried (MgSO₄),concentrated and purified by chromatography on silica gel (1%MeOH/CH₂Cl₂→10% MeOH/CH₂Cl₂) to give monoamidate 81-1 (5 mg, 3%) andbisamidate 81-2 (5 mg, 3%). For 81-1: ¹H NMR (300 MHz, CD₃OD) δ 7.78(1H, m), 7.35 (2H, m), 7.20 (3H, m), 4.18-3.95 (5H, m), 2.24-1.90 (2H,m), 1.87-1.62 (4H, m), 1.38-1.18 (6H, m), 1.02 (6H, m); ³¹P NMR (121MHz, CD₃OD) δ 36.3, 35.3; LC-MS (method: 0.5 min 95% H₂O/5% MeCN→5 min0% H₂O/100% MeCN, rt=2.18 min. MS calc'd for C₂₃H₃₄N₆O₅P (MH⁺): 505.2.Found 505.2. For 81-2: ¹H NMR (300 MHz, CD₃OD) δ 7.77 (1H, s), 4.23-3.92(8H, m), 2.04-1.50 (6H, m), 1.42 (3H, d), 1.40 (3H, d), 1.28 (3H, t),1.22 (3H, t), 1.02 (3H, s), 1.01 (3H, s); ³¹P NMR (121 MHz, CD₃OD) δ33.9; LC-MS (method: 0.5 min 95% H₂O/5% MeCN→5 min 0% H₂O/100% MeCN,rt=1.79 min. MS calc'd for C₂₂H₃₉N₇O₆P (MH⁺): 528.3. Found 528.3.

The diacid (25 mg, 0.072 mmol), amino acid (25 mg, 0.16 mmol), phenol(38 mg, 0.40 mmol), and triethylamine (127 μL, 0.911 mmol) weredissolved in pyridine (1.25 mL). The mixture was heated to 60° C. for 5minutes. To this reaction mixture was added a solution oftriphenylphosphine (140 mg, 0.534 mmol) and Aldrithiol(2) (119 mg, 0.540mmol) dissolved in pyridine (1.25 mL). The reaction was then heated at60° C. for 12 hours. Another batch of diacid (12 mg, 0.035 mmol) wastreated as described above. The reaction mixtures from both batches werecombined and diluted in EtOAc, washed with H₂O, sat'd NaHCO₃(aq) andbrine. The organic layer was dried (MgSO₄), concentrated and purified bychromatography on silica gel (1% MeOH/CH₂Cl₂→10% MeOH/CH₂Cl₂). to givemonoamidate 81-3 (3 mg, 8%) and bisamidate 81-4 (8 mg, 20%). For 81-3:¹H NMR (300 MHz, CD₃OD) δ 8.38-8.08 (1H, m), 7.78-7.60 (2H, m),7.50-7.18 (8H, m), 6.67-6.05 (1H, m), 5.60-5.30 (2H, m), 4.63 (1H, bs),4.25-3.95 (3H, m), 1.37 (3H, m), 1.18 (3H, m); ³¹P NMR (121 MHz, CD₃OD)δ 21.5, 20.2; LC-MS (method: 0.5 min 95% H₂O/5% MeCN→5 min 0% H₂O/100%MeCN, rt=1.98 min. MS calc'd for C₂₅H₂₈N₆O₅P (MH⁺): 523.2. Found 523.2.For 81-4: ¹H NMR (300 MHz, CD₃OD) δ 8.15 (1H, dd), 7.72 (1H, s), 7.67(1H, m), 7.39 (2H, m), 7.28 (1H, m), 6.44 (1H, dd), 5.40 (2H, s),4.23-3.90 (6H, m), 1.42 (6H, m), 1.27 (3H, t), 1.18 (3H, t); ³¹P NMR(121 MHz, CD₃OD) δ 19.7; LC-MS (method: 0.5 min 95% H₂O/5% MeCN→5 min 0%H₂O/100% MeCN, rt=1.86 min. MS calc'd for C₂₄H₃₃N₇O₆P (MH⁺): 546.2.Found 546.2.

Pro-Drug Cleavage Assays Isolation of PBMC Extracts:

Fresh human PBMCs were obtained from patients undergoing leukophoresis;cells were shipped in plasma and processed within 26 h of draw.Purification was achieved using the Ficoll-Paque method: PBMC cells wereharvested by centrifugation at 1200×g for 5 minutes and washed threetimes by re-suspension in RBC lysis buffer (155 mM NH₄Cl, 0.1 mM EDTA,10 mM KHCO₃). Washed cells were suspended in lysis buffer (0.2×10⁹ cellsin 1 ml of 10 mM Tris, pH 7.4, 150 mM NaCl, 20 mM CaCl₂, 1 mM DTT and 1%NP40) and incubated on ice for 20 minutes. The PBMC crude extract wascentrifuged at 1000×g for 30 min to remove unlysed cells and thesupernatant at 100,000 X g for 1 h. The 100,000×g supernatant (PBMCExtract: P0) was harvested, snap frozen in liquid nitrogen and stored at−70° C.

Protocol for Measurement of Cleavage of Prodrugs by PBMC Extracts:

Reaction mixtures contained 25 mM MesNa (pH 6.5), 100 mM NaCl, 1 mM DTT,0.1% NP-40, 30 μM substrate, and varying amounts of enzyme in a finalvolume of 100 μl. The enzymatic reaction is performed at 37° C. for10-120 minutes and stopped at 3-4 individual time points by adding 180μl of ice cold methanol. Samples are incubated at −20° C. for 30 min,and centrifuged 13,000 RPM for 30 min (at 4° C.). The supernatant istransferred to a 96 well plate and evaporated under vacuum using aspeedvac. The precipitate is dissolved in 100 μl of 20 mM CH₃COONH₄+5%AcCN. The disappearance of pro-drug is measured by HPLC, monitoring at260 nm. The specific activity of the PBMC Extract against the prodrugstested is defined as: v (cleavage rate)/μg protein=pmoles/min/μg.

Results

Human PBMC extract specific activity Compound (pmol/min/μg) 81-1 3.4881-2 0.65 81-3 4.9 81-4 0.38

Example 82 Preparation of Exemplary Compounds of the Present Invention

A series of inhibitors of PNP are rationally designed to mimic thetransition state of the enzyme. This class as a whole is called theImmucillins. Depending on the enzyme that is used for the rationaldesign of inhibitors, slightly different structures were proposed andsynthesized. A highly potent analog inhibiting the PNP enzyme fromMycobacterium tuberculosis (MtPNP) called DADMe-ImmG, structure below,was prepared recently (Lewandowics A. et al., Biochemistry, (2003), 42,6057).

Reduction of the dose and/or improvement of efficacy is achieved by theuse of pro-drugs DADMe-ImmG that, upon cleavage inside the target cell,give rise to agents with increased intracellular half-lives. Suchphosphonates pro-drug compounds are shown below (Scheme 82.2).

Compounds such as 82-1 is made according to the general route outlinedin Scheme 82.3, with an example depicted in Scheme 82.4.

Preparation of DADMe-ImmG is reported in Lewandowics A. et al.,Biochemistry, (2003), 42, 6057. The tertiary nitrogen of the ring maynot interfere with the alkylation of the secondary alcohol and in thatcase does not need to be protected, although standard protection anddeprotection protocols as described in Greene, T. Protective groups inorganic synthesis, Wiley-Interscience, (1999) may be used if necessary.Reaction of the primary alcohol 82-3 with base followed by addition ofthe appropriately activated phosphonate yields the protected product.Global deprotection yields the desired phosphonate 82-4.

Compounds such as 82-2 is made according to the general route outlinedin Scheme 82.5, with an example depicted in Scheme 82.6.

Preparation of DADMe-ImmG is reported in Lewandowics A. et al.,Biochemistry, (2003), 42, 6057. Blocking of the primary alcohol can beachieved by methods described in Greene, T., Protective groups inorganic synthesis, Wiley-Interscience, (1999). Reaction of the secondaryalcohol in base followed by addition of the appropriately activatedphosphonate yields the protected desired product. Deprotection yieldsthe desired phosphonate.

Specifically, the protected DADMe derivative can be treated with treatedin a solvent such as tetrahydrofuran or dimethylformamide with a basesuch as sodium hydride. When bubbling ceases, diethylphosphonoethylltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, yielding the desired phosphonate ester.Removal of the protecting group can be performed as described in Greene,T., Protective groups in organic synthesis, Wiley-Interscience, (1999)to provide the desired phosphonate ester.

Example 83 Preparation of Exemplary Compounds of the Present Invention

A synthetic scheme towards specific targets 83-8 and 83-9 is outlinedbelow: Scheme 83.2

Reference for these reactions: J. Med. Chem. (1996), 39, 4608Additional Compounds: The synthesis of targets 83-13 and 83-14 is setforth below.

Example 84 Preparation of Exemplary Compounds of the Present Invention

Leflunomide (structure below, together with its active metabolite) (seeU.S. Pat. No. 4,284,786) is a derivative of isoxazole that inhibitsvarious T-lymphocyte functions through the inhibition of dihydroorotatedehydrogenase (Copeland et al, Biochem., (1996), 35, 1270).

The active metabolite of leflunomide (A771726, also known asteriflunomide, see U.S. Pat. No. 6,288,098) has a very long half-life inhumans, and this is a cause for concern given the side effects that havebeen noted for the compound, which include skin rash, pruritus,diarrhea, abdominal pain, nausea, vomiting, weight loss, hypertension,dizziness, and reversible alopecia. More serious adverse events thathave also been reported include several cases of pleural involvement,vasculitis and hepatotoxicity. Rare cases of Stevens-Johnson syndromeand toxic epidermal necrolysis have also been described.

Reduction of the dose and improvement of efficacy is achieved by the useof pro-drugs of analogs of leflunomide or its metabolite which, uponcleavage inside the target cell, give rise to an agent with an increasedintracellular half-life. The same concepts are applicable to FK778(MNA-715) (see U.S. Pat. No. 5,308,865), an agent with a similar mode ofaction. Such compounds are described below.

Synthetic methodology towards compounds such as these is described byWestwood et al, J. Med. Chem., (1996), 39, 4608-4621, according to thegeneral routes outlined in Schemes 84.3-84.5.

Examples of the synthesis of suitable phosphonate-containing anilinesare shown below.

Example 85 Preparation of Exemplary Compounds of the Present Invention

Brequinar (structure below; see U.S. Pat. No. 4,680,299 and U.S. Pat.No. 5,032,597) is an inhibitor of dihydroorotate dehydrogenase(Biochemical Pharmacology 1990, 40, 709-714).

The compound has been investigated clinically as an immunosuppressant oras an anti-cancer agent, but its efficacy has been disappointing,possibly due to a narrow therapeutic window arising from an excessivelylong half-life that precludes higher dosing.

These problems are addressed by the use of pro-drugs of analogs ofbrequinar as well as other quinoline inhibitors of dihydroorotatedehydrogenase which, upon cleavage inside the target cell, give rise toan active entity with a sustained intracellular half-life relative toplasma levels. The therapeutic index of such agents might besignificantly improved over brequinar itself. Such compounds aredescribed below.

Synthetic methodology towards compounds such as these is based onmethods described by Batt et al, Bioorg. Med. Chem. Lett., (1995), 5,1549. A typical general route is outlined in Schemes 85.3-85.5.

Examples of the synthesis of suitable phosphonate-containing analogs areshown below.

Example 86 Preparation of Exemplary Compounds of the Present Invention

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) wasadded diethyl cyanophosphonate (34.8 μL, 230 μmol) anddiisopropylethylamine (Hunig's Base, DIEA, 30.4 μL, 177 μmol). Thesolution was stirred at ambient temperature for 4 hours whendiethyl(aminomethyl)-phosphonate (45.4 mg, 177 μmol) was added. Thesolution was stirred for 4 additional hours, when complete consumptionof the starting materials was observed. The reaction was worked up byremoval of the solvent in vacuo and purifying the residue by silica gelchromatography using MeOH—CH₂Cl₂ (10-30%). The product collected fromthis chromatography step was sufficiently pure to be carried on to thenext reaction. A small amount of the product (20 mg) was repurified byRP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 12.9 mg(76%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 6H,J=7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J=7.2 Hz), 4.81 (s,2H), 6.81 (d, 2H, J=9 Hz), 7.71 (d, 2H, J=9 Hz), 8.40 (br s, 1H), 8.61(s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.4. MS (m/z) 475.2 [M+H]⁺, 597.2[M+Na]⁺.

To a solution of crude(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (60 mg, 126 μmol)in dry DMF (0.90 mL) was added trimethylsilyl bromide(bromotrimethylsilane, TMSBr, 130.6 μL, 1,010 μmol) at ambienttemperature. The solution was then heated at 70° C. for 4.0 hours, afterwhich the reaction mixture was allowed to cool to room temperature. Thesolvent volume was reduced to ˜700 μL in vacuo and diluted with H₂O (100μL). This solution was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 26.8 mg (51%) of the desiredcompound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H),3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.79 (d, 2H, J=9 Hz),8.07 (br s, 1H), 8.56 (s, 1H); MS (m/z) 419.2 [M+H]⁺.

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 4 hours,when diethyl(aminoethyl)phosphonate (43.8 mg, 161 μmol) was added. Thesolution was stirred for 3 additional hours, by which time completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The productcollected from this chromatography step was sufficiently pure to becarried on to the next reaction. A small amount of the product (32 mg)was re-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%)to provide 19 mg (70%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m,2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz),7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). ³¹P (121.4 MHz,DMSO-d₆) δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺.

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (61 mg, 125 μmol)in dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 μmol) at ambienttemperature. The solution was then heated at 70° C. for 5.5 hours, whenLCMS analysis demonstrated the reaction to be 90% complete. The reactionmixture was allowed to cool to room temperature and stirred for anadditional 12 hours. The reaction was worked up by removal of thesolvent in vacuo and dissolving the residue in DMF/H₂O (800 μL, 1:1) and1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (2-95%) to provide 29 mg (53%) of thedesired compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71(br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H),8.15 (br s, 1H), 8.56 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS (m/z)431.3 [M−H]⁻.

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 3 hours,when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added.The solution was stirred for 2 additional hours, whereupon completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The product(65.5 mg) collected from this chromatography step was sufficiently pureto be carried on to the next reaction. A small amount (32.8 mg) wasre-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 23.2 mg (75%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H),3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz),7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 31.9; MS (m/z) 503.2 [M+H]⁺.

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester post silica column chromatography (32.2 mg, 66.2μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) atambient temperature. The solution was then heated at 70° C. for 1.0hour, when LCMS analysis demonstrated the reaction to be complete. Thereaction mixture was allowed to cool to room temperature, and water (60μL) and methanol (60 μL) were added. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 11.2 mg (38%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40(m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20(br s, 1H), 8.69 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z)447.3 [M−H]⁻.

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) wereadded diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL,474.9 μmol). The solution was stirred at ambient temperature for 3.5hours, when a solution of(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionic acid ethyl estermono acetic acid salt (57.1 mg, 158.3 mmol; mixture of diastereomers atphosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5additional hours, whereupon complete consumption of the startingmaterials was observed. The solvent was removed in vacuo and the crudematerial was purified by silica gel chromatography using MeOH—CH₂Cl₂(10-30%). A small amount of the product (24.8 mg) was repurified by RPHPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 15.8 mg(65%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.27 (m,3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19(s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H),6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66(d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 26.6, 27.4. MS (m/z) 609.2 [M+H]⁺.

To a solution of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionicacid ethyl ester (mixture of diastereomers at phosphorus; 40.0 mg, 65.7μmol) in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL) wasadded aqueous sodium hydroxide (1 N, 131.4 μL). The solution was stirredat ambient temperature for 4 hours. The solvents were removed in vacuoand the crude product was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (d, 2H, J=6.9 Hz), 1.79 (m, 2H), 3.21(s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J=8.7Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹P (121.4MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺.

To a solution of4-[(2,4-diaminopteridin-6-ylmethyl)-methyl-amino]benzoic acidhemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL) wereadded diethyl cyanophosphonate (53.0 μL, 349.5 μmol) and DIEA (138.0 μL,806.7 μmol). The solution was stirred at ambient temperature for 2.5hours, whereupon (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionicacid ethyl ester mono acetic acid salt (diastereomerically pure atphosphorus; 268.9 μmol) in DMF (500 μL) was added. The solution wasstirred for 30 additional minutes, whereupon complete consumption of thestarting materials was observed. The solvent was removed in vacuo andthe crude material was purified by silica gel chromatography usingMeOH—CH₂Cl₂ (10-30%). A small amount of the product (40.0 mg) wasrepurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 28.7 mg (75.1%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.15 (t, 3H, J=7.2 Hz), 1.44 (d, 3H, J=6.9 Hz), 2.26 (m, 2H), 3.23 (s,3H), 3.51 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H),6.81 (d, 2H, J=9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J=9.3Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6. MS(m/z) 609.2 [M+H]⁺.

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL) wereadded diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL,209.4 μmol). The solution was stirred at ambient temperature for 3hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acidethyl ester mono acetic acid salt (mixture of diastereomers atphosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution wasstirred for 30 minutes when complete consumption of the startingmaterials was observed. An aliquot (66%) of the reaction was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%), yielding 27.2 mgof crude product. A small amount of the product (10 mg) was repurifiedby RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 4.2mg (26%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (t, 3H,J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51(m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80(d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d,2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆) δ29.5, 30.1. MS (m/z) 608.2 [M+H]⁺.

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL) wereadded diethyl cyano phosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL,498.6 μmol). The solution was stirred at ambient temperature for 3.5hours when (L)-2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2μmol) was added. The solution was stirred for 48 additional hours. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct (87 mg) collected from this chromatography step was sufficientlypure to be carried on to the next reaction. An aliquot of the product(51.0 mg) was repurified by RP HPLC on C₁₈ column using H₂O/acetonitrile(2-95%) to provide 24.7 mg (44%) of the pure product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.18 (t, 6H, J=6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s,3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d,2H, J=9 Hz), 7.73 (d, 2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.56 (s, 1H);³¹P (121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3 [M]⁺.

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino})-2′(L)-(6′-(phosphonic acid diethyl ester) hexanoic acid) post silicacolumn chromatography (20 mg, 34.6 μmol) in dry DMF (0.60 mL) was addedTMSBr (18.0 μL, 139.2 μmol) at ambient temperature. The solution wasthen heated at 70° C. for 18 hours, after which the reaction mixture wasallowed to cool to room temperature. The solvent was removed in vacuoand dissolved in DMF (400 μL) and water (60 μL). This solution waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 8.9 mg (49%) of the product as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77(s, 2H), 6.62 (br s, 1H), 6.80 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8.7Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS (m/z) 519.2 [M+H]⁺.

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester can be prepared asfollows.

a. (L)-2-Cbz-Amino-hexanoic acid-6-phosphonic acid

To a suspension of (L)-2-amino-6-(diethoxyphosphonyl)hexanoic acid (106mg, 396.8 μmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μL, 2,381.0μmol) at ambient temperature. The solution was then heated at 70° C. for2 hours, after which the reaction mixture was allowed to cool to roomtemperature. The solvent was removed in vacuo. The crude material wasdissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzylchloroformate (79.3 μL, 555.5 μmol) was added and stirring at roomtemperature was continued. After 2 hours, the solution was washed withether (2 mL) and the aqueous layer was acidified with aqueous HCl topH 1. The aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried over sodium sulfate. Filtration andevaporation of solvents yielded a crude product, which was sufficientlypure for further transformations. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.65(m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z) 345.6 [M+H]⁺.

b. (L)-2-Aminohexanoic acid 2′ TMS ethyl ester-6-phosphonic acid monophenyl ester

To a solution of (L)-2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3mg, 397.9 μmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50μL). Stirring at room temperature was continued. After 22 hours completeconversion was observed. The solvents were removed in vacuo. The crudematerial was sufficiently pure for the next step.

One half of the crude material (198.9 μmol) was dissolved in toluene(3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol)was added and the reaction mixture was heated at 70° C. (oil bath).After 4 hours, the reaction was cooled to room temperature and thesolvent was removed in vacuo. The crude material was re-dissolved inmethylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) wasadded. Stirring at room temperature was continued. After 4 hrs thesolvents were removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) andaqueous sodium hydroxide solution (1N, 0.885 mL) was added. Stirring atroom temperature was continued. After 14 hours the solvent was removedin vacuo to provide the crude phosphonate mono phenyl ester (63.8 mg).This material was dissolved in 2-TMS ethanol (1.0 mL) and acetylchloride (20 μL) was added. Stirring at room temperature was continued.After 22 hours complete conversion to the carboxylate ester wasobserved. The solvents were removed in vacuo. The material wassufficiently pure for the next step.

One half of the crude material (75 μmol) was dissolved in ethanol (1.5mL). Pd/C (5%, 20 mg) was added and the reaction was placed under anatmosphere of hydrogen gas. After 1.5 hours Celite was added and thecrude reaction mixture was filtered through Celite. The solvents wereremoved in vacuo and the crude material was used in the next stepwithout further purification.

c.2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (22.7 mg, 60.0 μmol) in DMF (0.80 mL) wereadded diethyl cyano phosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL,180.0 μmol). The solution was stirred at ambient temperature for onehour when (L)-2-amino-6-monophenoxyphosphonatohexanoic acid 2′ TMS ethylester (70.5 μmol), suspended in DMF (0.2 mL), was added. The solutionwas stirred for 3.5 additional hours. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (5-95%) toprovide 19.4 mg (46%) of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester. ¹H NMR (300 MHz,DMSO-d₆) δ 0.0 (s, 9H), 0.91 (t, 2H, J=8.1 Hz), 1.42-1.53 (m, 4H),1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J=8.1 Hz), 4.29 (m, 1H),4.86 (s, 2H), 6.81 (d, 2H, J=9 Hz), 7.12 (m, 3H), 7.31 (m, 2H), 7.74 (d,2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.71 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 26.2; MS (m/z) 695.2 [M]⁺.

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester can be prepared as follows.

2-{4-[(2,4-Diaminopteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester

To a solution of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol,Example 225) in DMF (0.70 mL) was added PyBOP (32.4 mg, 62.4 μmol), DIEA(21.4 mg, 166.4 μmol) and (S) ethyl lactate (19.6 mg, 166.4 μmol). Thereaction mixture was stirred at room temperature for one hour. The crudereaction mixture was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (5-95%) to provide 13.5 mg (81%) of the pure product asa mixture of diastereomers at phosphorus (4:1). ¹H NMR (300 MHz, CDCl₃)δ 0.0 (s, 9H), 1.02 (t, 2H, J=8.7 Hz), 1.23 (t, 3H, J=9.3 Hz), 1.35 (d,2.4H, J=6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H),4.03-4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57(d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30 (m, 2H), 7.63 (d,2H, J=7.5 Hz), 8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 30.5, 29.2; MS(m/z) 795.2 [M]⁺.

Example 87 Preparation of Exemplary Compounds of the Present Invention

A recent PNP inhibitor PNP-405 (also described as PNU-405) was disclosedin the ACS meeting, (2000). This compound inhibits purine nucleotidephosphorylase with an IC₅₀ of 20 nM (structure below).

Reduction of the dose and/or improvement of efficacy is achieved by theuse of pro-drugs PNP-405 that, upon cleavage inside the target cell,give rise to agents with increased intracellular half-lives. Suchphosphonates pro-drug compounds are shown below (Scheme 87.2).

Compounds such as 87-2, 87-5 are made according to the general routeoutlined in Scheme 87.3, with an example depicted in Scheme 87.4.

PNP-405 is prepared according to the method of Littler, B. J. et al.,7^(th) International Conference on Organic Process Research andDevelopment, New Orleans, La., Mar. 16-19, (2003). PNP-405 is treated ina solvent such as tetrahydrofuran or dimethylformamide with a base suchas sodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., (1986), 27, 1477) is added, toprovide compound 87-6 as the desired product.

Compounds of Scheme 87.2 where X=O, Z=CH₂OH), can be prepared accordingto the procedure of Littler, B. J. et al., 7^(th) InternationalConference on Organic Process Research and Development, New Orleans,La., Mar. 16-19, (2003) (Schemes 87.5 and 87.6). The starting material,2-benzyloxyphenylacetic acid (provided by Avocado) can be acylated viathe mixed anhydride with the oxazolidinone shown at 80-85° C., withtriethylamine as base. A low-temperature alkylation withbromoacetonitrile results in the formation of compound 87-9 with gooddiastereomeric ratio. Removal of the chiral auxiliary under reductiveconditions yields compound 87-10 without racemization. Protection of theresulting alcohol with the trityl group provides compound 87-11.Subsequent pyrrole ring construction as well as cyclo-guanidinylationreaction to prepare the six-membered 2-aminopyrimidone ring can beprepared as illustrated in Scheme 87.6.

Compounds of Schemes 87.2 (where X=O, Z=H) can be prepared according tothe general route illustrated above. The starting material,3-(2-Benzyloxy-phenyl)-propionitrile, is available by Lewisacid-mediated reaction of phenol with acrylonitrile according to U.S.Pat. No. 2,789,995, published in 1954. Intermediate 87-11 can follow thesame synthetic steps as outlined here to provide of compounds of Schemes87.1 and 87.1.

Pyrrole ring construction can be completed in three steps from3-(2-Benzyloxy-phenyl)-propionitrile. Formation of3-hydroxy-acrylonitrile 87-13 can be achieved by exposure of 87-12 toLDA and ethyl formate. Condensation of this product with 2-Amino-malonicacid diethyl ester in EtOH and sodium acetate yields compound 87-14which undergoes a decarboxylative cyclization in the basic medium ofNaOH and EtOH to provide pyrrole 87-15. In some syntheses, the tritylprotecting group on the benzylic alcohol is removed at this stage.Subsequently, guanidinylation reaction using cyanamide provides compound87-16 which, upon treatment with sodium hydroxide, cyclizes to form the2-aminopyrimidone ring (compound 87-17). Removal of the phenolicprotecting group under hydrogenolysis conditions provides the freephenol, which is used as the attachment site for the pro-drug group. Avariety of linkers may be utilized to attach the pro-drug moiety to thebackbone molecule. A particular example in which diethylphosphonomethyltriflate is used as the starting materials is illustratedbelow. Therefore, compound 87-18 is treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydrideor cesium carbonate. When bubbling ceases, diethylphosphonomethyltriflate (prepared according to Tetrahedron Lett.,(1986), 27, 1477) is added, to provide compounds of Scheme 87.2.

Compounds of Schemes 87.2 (where X=O, Y=H, Z=CH₂OH) can be prepared from4-benzyloxyphenylacetic acid (available from Aldrich). Following asimilar sequence to that demonstrated in Scheme 87.7, intermediate 87-24can be prepared (Scheme 87.7). Proceeding with the sequence shown inSchemes 87.6, 87-24 can be transformed to the desired products of Scheme87.2.

Example 88 Preparation of Exemplary Compounds of the Present Invention

The phosphorus containing thiazolidinedione derivative 88-2 issynthesized from parent compounds by alkylation. The parent compound88-1 is obtained by the procedure as described in U.S. Pat. No.4,572,912. Scheme 88.1 shows the attachment of the phosphonate linkageto the phenolic OH of 88-1 to give compounds of formula 88-2. Compound88-1 is dissolved in a suitable aprotic solvent such as, DMF and is thentreated with the phosphonate reagent (88-30), bearing a leaving group,for example, bromine, mesyl, tosyl, or trifluoromethanesulfonyl, in thepresence of a suitable organic or inorganic base. In the schemes of thisExample, A⁰-LG refers to a phosphonate compound as described is thisspecification that is attached to a leaving groups, such as, forexample, a halogen, a triflate, a mesylate, or a toluenenesulfonate.

For example, a solution of 88-3 in DMF is treated with cesium carbonateand one equivalent of (trifluoromethanesulfonyloxy)methylphosphonic aciddiethyl ester 88-18, 88-25 to give troglitazone-phosphonate 88-4 inwhich the linkage is a methylene group as shown in Scheme 88.2. Usingthe above procedure but employing a different 88-1 and phosphonatereagents 88-30, 88-40, the corresponding products 88-2 bearing differentsubstituents and linking groups can be obtained.

Scheme 88.3 shows the preparation of phosphorus containingthiazolidinedione derivative of type 88-7, 88-20. The parent compound88-5 is obtained by the procedure as described in U.S. Pat. No.4,572,912. The phenolic OH and thiazolidinedione unit are protected withsuitable protecting group, for example SEM group, and the hydroxyl groupat C4 position of chroman alcohol analogs is generated by reduction ofthe carbonyl group, using suitable reducing agent, for example sodiumborohydride. The alcohol 88-6 is then treated with suitablechloroformate ester, for example phenyl chloroformate or p-nitrophenylchloroformate, or carbonate, such as bis(p-nitrophenyl)carbonate togenerate an active carbonate. The resulting active carbonate is reactedwith phosphonate reagents bearing amino group 88-35 and subsequentdeprotection of protecting groups produces the phosphonates of type88-7, 88-20.

For example, a solution of 88-8 in THF is treated withdiisopropylethylamine and two equivalent of2-(trimethylsilyl)ethoxymethyl chloride to protect the phenolic OH andthiazolidinedione unit. A solution of the protected product in methanolis then reduced using sodium borohydride to obtain the alcohol 88-9. Thealcohol 88-9 is treated with phenyl chloroformate to provide phenylcarbonate, which is reacted with 2-aminoethylphosphonate diethyl ester88-12, to obtain protected phosphonate derivative, which is deprotectedby tetrabutylammonium fluoride in THF to result 88-10. Using the aboveprocedure but employing different 88-5 and phosphonate reagents 88-35the corresponding products 88-7, 88-20 bearing different substituentsand linking groups can be obtained.

Scheme 88.5 shows the preparation of phosphorus a containingthiazolidinedione derivative. Thiazolidinedione with phosphoruscontaining moiety 88-13 is generated by the alkylation ofthiazolidinedione 88-11 in a suitable aprotic solvent such as, DMF andis then treated with the phosphonate reagent 88-30, 88-40, bearing aleaving group, for example, bromine, mesyl, tosyl, ortrifluoromethanesulfonyl, in the presence of a suitable organic orinorganic base. Compound 88-13 is then reacted with benzaldehyde 88-14with protected phenol at the para position. The protecting group R⁸⁸ canbe any protecting group for phenolic OH, for example alkoxyalkyl groups,such as the methoxymethyl group; aralkyl groups, such as the benzylgroup; the 2-tetrahydropyranyl group; and acyl groups, such as theacetyl or benzoyl groups, preferably benzyl group. The reaction iscarried out in an aprotic solvent, such as toluene, suitably at anelevated temperature, such as the reflux temperature of the solvent, andpreferably in the presence of a suitable catalyst, such as piperidiniumacetate or benzoate. Favorably, the water produced in the reaction isremoved from the reaction mixture, for example by means of a Dean andStark apparatus. The reduction of 88-15 to 88-16 is accomplished bycatalytic reduction with suitable catalysts, such as palladium on carboncatalysts, preferably a 10% palladium on charcoal catalyst. (U.S. Pat.No. 6,288,095) The coupling of 88-16 with chroman alcohol homolog 88-17,which is obtained by the procedure described in J. American Oil ChemicalSociety (1974), 51, 200 or in U.S. Pat. No. 4,572,912, and in which thealcoholic functional groups are suitably protected as described in U.S.Pat. No. 4,572,912, is done using Mitsunobu condition.

For example, a solution of 88-11 in DMF is treated with sodium hydrideand one equivalent of (trifluoromethanesulfonyloxy)methylphosphonic aciddiethyl ester 88-18, 88-25 to give thiazolidinedione-phosphonate 88-19in which the linkage is a methylene group as shown in Scheme 88.6. Thethiazolidinedione-phosphonate 88-19 is then reacted with thebenzaldehyde 88-20 bearing benzyloxy substituent in toluene in refluxcondition in the presence of catalytic piperidinium acetate withDean-Stark apparatus, which results 88-21. The reduction of 88-21 indioxane by catalytic hydrogenation in the presence of 10% palladium oncharcoal provides 88-22. The reaction between 88-22 and chroman alcoholanalogs 88-23 in the presence of diethyl azodicarboxylate andtriphenylphosphine followed by deprotection of SEM group by TBAFprovides 88-24. Using the above procedure but employing differentchroman alcohol analogs and phosphonate reagents 88-30, 88-40 thecorresponding products 88-2 bearing different substituents and linkinggroups are obtained.

Example 89 Preparation of Exemplary Compounds of the Present Invention

Schemes K2-K4 illustrate the syntheses of phosphonate compounds of theinvention, K2-K4, and of the intermediate compounds necessary for theirsynthesis.

Protection of Reactive Substituents.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the described sequence is reacted, and to deprotectthe substituents afterwards, according to the knowledge of one skilledin the art. Protection and deprotection of functional groups aredescribed, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990. The protectionand deprotection of steroidal ketones and alcohols is described inOrganic Reactions in Steroid Chemistry, Vol. 1, J. Fried and J. A.Edwards, van Nostrand Reinhold, 1972, p. 375ff. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [O], etc.

For example, Scheme K1 depicts a protection-deprotection sequence inwhich the steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety. In this sequence,6a,9α-difluoro-16β-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,21-dioneK1.1 (U.S. Pat. No. 4,619,921) is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative K1.2. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester K1.3. The BMD moiety is thenhydrolyzed, for example by treatment with 50% aqueous acetic acid, asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to afford the triolK1.4. The latter compound is then converted into the 17,21-cyclicorthoester K1.5 using the procedure described in Chem. Pharm. Bull.,1986, 34, 1613. The substrate is reacted in dimethylformamide at 70° C.with two molar equivalents of triethyl orthopropionate and a catalyticamount of p-toluenesulfonic acid. The product is then reacted with anexcess of trimethylsilyl chloride in dimethylformamide at ambienttemperature to produce the 21-chloro 17-propionate product K1.6.

Alternatively, the substrate K1.4 is converted into the product K1.6 bymeans of the method described in J. Med. Chem., (1987), 30: 1581. Inthis procedure, the 21-hydroxy group is activated by conversion to the21-mesylate, by reaction with mesyl chloride in pyridine; the mesylategroup is then displaced to yield the 21-chloro intermediate, by reactionwith lithium chloride in dimethylformamide, and the 17-hydroxyl group isesterified to give the 21-chloro-17-propionate derivative K1.6. Theselective acylation of the 17α hydroxyl group in the presence of an 11βhydroxyl group is described in J. Med. Chem., (1987), 30: 1581.

Preparation of the Phosphonate Esters K2.

Scheme K2 depicts the preparation of phosphonates K2 in which thephosphonate is attached by means of an imino or iminoxy group and avariable carbon chain. In this procedure, the BMD-protected derivativeK1.2 is reacted with an amine or hydroxylamine K2.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., (1978), 86, 133. and in J. Mass. Spectrom., (1995), 30, 497. TheBMD-protected side-chain compound K2.2 is then converted into the triolK2.3a, and then to the 21-chloro 17 propionate product K2.3b, asdescribed in Scheme K1.

Scheme K2 also illustrates the preparation of hydroxylamine ethersincorporating a phosphonate group. In this procedure, a phosphonateK2.4, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine K2.5(Aldrich) to produce the ether K2.6. The reaction is conducted betweenequimolar amounts of the reactants in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such aspotassium hydroxide or dimethylaminopyridine. Deprotection, for exampleby treatment with trifluoroacetic acid, then gives the hydroxylamineether K2.7.

Scheme K2, Example 89-A illustrates the preparation of phosphonates K2in which the phosphonate is attached by means of an iminoxy group. Inthis procedure, the substrate K1.2 is reacted with a dialkylphosphonomethyl hydroxylamine K2.8, prepared as described above from adialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett. 27:1477(1986)) and BOC-hydroxylamine, to afford the oxime K2.9. Deprotectionthen affords the triol K2.10a from which the 21-chloro 17-propionatecompound K2.10b is prepared. The oxime forming reaction is performed atambient temperature in ethanol-acetic acid solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether K2.8, different oxime ethers K2.1, the corresponding productsK2.3b are obtained.

Scheme K2, Example 89-B illustrates the preparation of compounds K2 inwhich the phosphonate group is attached by means of a thienylmethoxyoxime group. In this procedure, the dienone K1.2 is reacted, asdescribed above, with O-(4-bromo-2-thienylmethoxy)hydroxylamine K2.11,prepared as described above from 4-bromo-2-bromomethylthiophene (WO9420456) and BOC-protected hydroxylamine, to give, after deprotection ofthe side-chain, the oxime K2.12. The product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphite K2.13 toafford the phosphonate K2.14a. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem. 35:1371 (1992). The reaction isperformed in an inert solvent such as toluene, in the presence of a basesuch as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0). The 21-hydroxy compound K2.14ais then converted, as described in Scheme KI, into the 21-chloro17-propionate derivative K2.14b.

Alternatively, the bromo compound K2.12 is coupled with a dialkylbutenyl phosphonate K2.15 (Org. Lett. 3:217 (2001)) to afford thephosphonate K2.16a. The coupling of aryl halides with olefins by meansof the Heck reaction is described, for example, in F. A. Carey and R. J.Sundberg, Advanced Organic Chemistry 503ff (Plenum, 2001) and in Acc.Chem. Res. 12:146 (1979). The aryl bromide and the olefin are coupled ina polar solvent such as dimethylformamide or dioxan, in the presence ofa palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the double bond present in the product K2.16a is reduced,for example by reaction with diimide, to produce the saturated analogK2.17a. The reduction of olefinic bonds is described in R. C. Larock,Comprehensive Organic Transformations 6ff (VCH 1989). The transformationis effected by means of catalytic hydrogenation, for example using apalladium on carbon catalyst and hydrogen or a hydrogen donor, or by theuse of diimide or diborane. The products K2.16a and K2.17a are thenconverted into the 21-chloro 17-propionate analogs K2.16b and K2.17b.

Using the above procedures, but employing, in place of thebromothienylmethoxy reagent K2.11, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds K2.14b, K2.16b andK2.17b are obtained.

Scheme K2, Example 89-C depicts the preparation of phosphonates K2 inwhich the phosphonate is attached by means of an imino group. In thisprocedure, the substrate K1.2 is reacted with a dialkyl4-amino-2-thienyl phosphonate K2.18, prepared by the palladium-catalyzedcoupling, as described above, between 4-amino-2-bromothiophene (Tet.43:3295 (1987)) and a dialkyl phosphite, to give, after deprotection,the imine product K2.19a. The imine forming reaction is conducted in ahydrocarbon solvent such as toluene or xylene, at reflux temperature, inthe presence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.The product is then converted into the 21-chloro 17-propionate compoundK2.19b.

Using the above procedures, but employing, in place of the4-aminothienyl phosphonate K2.18 different amino-substituted aryl orheteroaryl phosphonates, products analogous to K2.19b are obtained.

Scheme K2, Example 89-D illustrates the preparation of phosphonates K2in which the phosphonate is attached by means of an oximino group and anamide linkage. In this procedure, the dienone K1.2 is reacted withO-(4-aminobutyl)hydroxylamine K2.20 (Pol. J. Chem. 55:1163 (1981)) toyield the oxime K2.21. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch. 7:795(1976); the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The productis then coupled with a dialkyl 2-hydroxyethyl phosphonate K2.22(Epsilon) and carbonyl diimidazole, to yield the carbamate oxime K2.23.The preparation of carbamates is described in A. R. Katritzky,Comprehensive Organic Functional Group Transformations,6:416ff(Pergamon, 1995), and in S. R. Sandier and W. Karo, OrganicFunctional Group Preparations, 260ff (Academic Press, 1986). In theprocedure, the amine is reacted in an inert aprotic solvent such asdichloromethane or tetrahydrofuran, with phosgene or a functionalequivalent thereof, such as carbonyl diimidazole, triphosgene,pentafluorophenyl carbonate and the like, to afford the correspondingactivated acylamine. The latter compound is then reacted with an alcoholto yield the carbamate. The carbamate product K2.23 is then converted,as described in Scheme K1, into the 21-chloro 17-propionate productK2.24b.

Using the above procedures, but employing, in place of the hydroxylamineK2.22, different amino-substituted hydroxylamines, and/or differenthydroxy-substituted phosphonates, the products analogous to K2.24b areobtained.

Preparation of the Phosphonate Esters K3 and K4.

Scheme K3 illustrates the preparation of the phosphonate esters K3 andK4 in which the phosphonate group is attached to the 1′ or 2′ positionof the pyrazole ring, by means of an aromatic or heteroaromatic group, aheteroatom and/or a variable carbon chain. In this procedure, theBMD-protected dienone K1.2 is reduced to afford the 1,2-dihydro productK3.1. The catalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem. 44:602 (2001). The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc. 86:1520(1964), to afford the 2-formyl product K3.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine K_(3.3), inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazolesK3.4 and K3.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc. 86:1520 (1964). The pyrazolesK3.4 and K3.5 are then transformed, for example by the proceduresdescribed in Examples 89-E and 89-F, via the BMD-protected intermediatesK3.6 and K3.7, into the 21-chloro 17-propionate phosphonates K3.8b andK3.9b.

Scheme K3, Example 89-E illustrates the preparation of phosphonates K3and K4 in which the phosphonate is attached by means of an amidelinkage. In this procedure, the ketoaldehyde K3.2 is reacted, asdescribed above, with 3-carboxypropyl hydrazine K3.10 (Ind. J. Exp.Biol. 32:218 (1994)) to give the pyrazoles K3.11 and K3.12. The2′-substituted isomer K3.11 is then reacted in dimethylformamidesolution at ambient temperature with one molar equivalent of a dialkyl4-aminophenyl phosphonate K3.13 (Epsilon) and dicyclohexyl carbodiimide,to yield the amide K3.14. The preparation of amides from carboxylicacids and derivatives is described, for example, in S. R. Sandler and W.Karo, Organic Functional Group Preparations, 274 (Academic Press, 1968),and R. C. Larock, Comprehensive Organic Transformations, 972ff (VCH,1989). The carboxylic acid is reacted with the amine in the presence ofan activating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The BMD protecting group is then removed and the product is convertedinto the 21-chloro 17-propionate product K3.16b.

Alternatively, the 1-substituted pyrazole K3.12 is coupled, as describedabove, with a dialkyl aminomethyl phosphonate K3.17 (Interchim), toafford the amide K3.18. The product K3.18 is then deprotected to givethe triol K3.19a, and the latter compound is transformed into the21-chloro 17-propionate K3.19b.

Using the above procedures, but employing different amino-substitutedphosphonates, and/or different carboxy-substituted hydrazines, theproducts analogous to K3.16b and K3.19b are obtained. Thefunctionalization procedures are interchangeable between the pyrazolesubstrates K3.11 and K3.12.

Scheme K3, Example 89-F illustrates the preparation of the phosphonatesK3 and K4 in which the phosphonate group is attached by means of an arylring and a propenyl linkage. In this procedure, the ketoaldehyde K3.2 isreacted, as described above, with allyl hydrazine K3.20 (Zh. Org. Khim.,3:983 (1967)) to produce the pyrazoles K3.21 and K3.22. The1′-substituted isomer K3.21 is coupled, as described in Scheme K2, witha dialkyl 3-bromophenyl phosphonate K3.23 (Epsilon) to give thephosphonate K3.24. The product is then deprotected to afford the triolK3.25a which is converted into the 21-chloro 17-propionate compoundK3.25b.

Alternatively, the 2′-substituted pyrazole K3.22 is coupled, asdescribed above, with a dialkyl 5-bromo-2-thienyl phosphonate K3.26(Syn., 455 (2003)) to prepare the phosphonate K3.27 which isdeprotected, and the product is converted into the 21-chloro17-propionate analog K3.28b.

Using the above procedures, but employing, in place of the propenylhydrazine K3.20, different alkenyl hydrazines, and/or different dialkylbromo-substituted phosphonates, the products analogous to the compoundsK3.25b and K3.28b are obtained.

Scheme K4 depicts the preparation of the phosphonate esters K3 and K4 inwhich the phosphonate group is attached by means of a variable carbonlinkage. In this procedure, the ketoaldehyde K3.2 is reacted withhydrazine, to afford the pyrazole derivative K4.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 86:1520 (1964). The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound K4.2, in which R² and X are as defined above, to yield thealkylation products K4.3 and K4.4. The alkylation of substitutedpyrazoles is described, for example, in T. L. Gilchrist, HeterocyclicChemistry, 309 (Longman, 1992). The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts K4.3 and K4.4 are, except in cases where X is dialkylphosphono,converted into the phosphonates K4.5 and K4.6, using the proceduresdescribed herein, and deprotection/chlorination/acylation then affordsthe 21-chloro 17-propionate compounds K4.7b and K4.8b.

As shown in Scheme K4, Example 89-G, the pyrazole K4.1 is reacted with2-bromobenzyl bromide K4.9 to give the pyrazoles K4.10 and K4.11. Theproducts are then coupled, as described above, with a dialkyl phosphite,to afford after side-chain deprotection and modification, as describedabove, the 21-chloro 17 propionates K4.12b and K4.13b.

As shown in Scheme K4, Example 89-H, the pyrazole K4.1 is reacted intetrahydrofuran solution, as described above, with 4-bromomethylcyclohexanone K4.14 (WO 9737959) to give the alkylation products K4.14and K4.15. The 1-substituted isomer K4.15 is then reacted, in areductive amination reaction, with a dialkyl aminomethyl phosphonateK.19 (Interchim) and sodium cyanoborohydride, to yield, afterdeprotection and side-chain modification, the 21-chloro 17-propionateK4.17b.

The preparation of amines by means of reductive amination procedures isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 421 (VCH, 1989), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.,55:2552 (1990).

The 2′-substituted pyrazole K4.16 is subjected to the same series ofreaction to give the amine phosphonate K4.18b.

Using the above procedures, but employing differentbromomethyl-substituted aldehydes or ketones, and/or differentamino-substituted phosphonates, the products analogous to K4.17b andK4.18b are obtained.

Example 90 Preparation of Exemplary Compounds of the Present Invention

Schemes 1 and 2 illustrate syntheses of phosphonate compounds of thisinvention, M1 and M2, and of intermediate compounds necessary for theirsynthesis.

Protection of Reactive Substituents

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis (Second Edition, Wiley, 1991). The protection anddeprotection of steroidal ketones is described in J. Fried and J. A.Edwards, Organic Reactions in Steroid Chemistry, Vol. 1 375ff (vanNostrand Reinhold, 1972). Reactive substituents which may be protectedare shown in the accompanying schemes as, for example, [OH], [O], etc.

Preparation of the Phosphonate Esters M1

Scheme 1 depicts the preparation of phosphonates Ml (Compound 1 inScheme 1). Scheme 1, Example 90-A depicts an example of Scheme 1. InScheme 1, Example 90-A, the5-hydroxy-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide 1.1 (preparedaccording to U.S. Pat. No. 3,888,843) can be treated in a solvent suchas tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding thedesired phosphonate diester 1.

Preparation of the Phosphonate Esters M2

Scheme 2 illustrates the preparation of the phosphonate esters M2(Compound 2 in Scheme 2). Compound 2.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide can be prepared by addition of the imidazole base (JP Kokai76 88965) onto the 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosylchloride (Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1, 245;Montgomery, J. A. et al., J. Med. Chem., 1969, 12, 3, 498; and Iwamoto,R. H. et al., J. Med. Chem., 1963, 6, 684). Compound 2.1 is thenprotected on the imidazol-4-ol. Oxidation of the 5′-OH followed byelimination provides glycal 2.3 (see the procedure of Zemlicka J. etal., J. Am. Chem. Soc., 1972, 94, 9, 3213). Selenoetherificationprovides the protected phosphonate 2.4 (Kim, C. et al., J. Org. Chem.,1991, 56, 2642). Oxidative elimination of the phenylselenide (asdescribed in Kim, C. et al., J. Org. Chem., 1991, 56, 2642) followed bystereoselective dihydroxylation provides the diol 2.6. Finally, theprotecting group is removed to provide compound 2.

Scheme 2, Example 90-C illustrates the preparation of the phosphonatesM2 (Compound 2 in this example). Specifically, compound 2.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide, which can be prepared by addition of the imidazole base (JPKokai 76 88965; also Schipper, E. et al., Am. Chem. Soc., 1952, 74, 350)onto the 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosyl chloride(Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1, 245; Montgomery,J. A. et al., J. Med. Chem., 1969, 12, 3, 498; and Iwamoto, R. H. etal., J. Med. Chem., 1963, 6, 684) is first protected using a TBS group.Subsequent oxidation with PtO₂ proceeds to provide carboxylic acid 2.2.Decarboxylative elimination is achieved using dimethylformamidedineopentyl acetal in DMF at high temperature (Zemlicka J. et al., J.Am. Chem. Soc., 1972, 94, 9, 3213). Once the furanoid glycal 2.3 is inhand, it is treated with silver perchlorate in the presence ofdiethyl(hydroxylmethyl)phosphonate (Phillion, D. et al., TetrahedronLett., 1986, 27, 1477) to provide the phosphonate 2.4 (Kim, C. et al.,J. Org. Chem., 1991, 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides a diol withthe desired stereochemistry. Deprotection of the TBS group can beachieved using TBAF to provide compound 2.

Example 91 Preparation of Exemplary Compounds of the Present Invention

Example 91-A[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonicacid diethyl ester

A mixture ofN-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide(30 mg, 0.06 mmol, Zimmermann et al., Bioorg. Med. Chem. Lett. 1996, 6,1221), diethyl 2-bromoethylphosphonate (30 μL, 0.12 mmol) and K₂CO3 (20mg, 0.16 mmol) in 2.5 mL of DMF was heated at 110° C. for 8 hours whenmost of the starting materials were consumed as judged by LCMS analysis.The solid material was filtered off. The filtrate was diluted with waterand then extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated to dryness. The crude material was purified by silicagel chromatography using 10% MeOH/CH₂Cl₂ to provide 28 mg (55%) of thedesired product. ¹H NMR (300 MHz, CDCl₃) δ 1.32 (t, 6H), 1.92-20.3 (m,4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 (s, 2H), 4.05-4.14(m, 4H), 7.07 (s, 1H), 7.18 (d, 2H, J=5 Hz), 7.30 (dd, 1H, J=6, 8 Hz),7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H,J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70 (dd, 1H, J=2, 5 Hz), 9.25 (s,1H); ³¹P (121.4 MHz, CDCl₃) δ 30.5; MS (m/z) 644 [M+H]⁺.

Example 91-B[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonicacid

To a solution of[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonicacid diethyl ester (8 mg, 0.012 mmol) in DMF (1 mL) was added TMSBr (15μL, 0.12 mmol) at room temperature. The reaction was allowed to proceedat room temperature for 14 hours. Another portion of TMSBr (20 μL) wasadded and heated at 110° C. for 12 hours when completion of the reactionwas detected by LCMS. The reaction was cooled down to room temperatureand quenched with addition of MeOH. The reaction mixture was dried underreduced pressure and the residue was purified by RP HPLC using a C18column with a gradient of H₂O-Acetonitrile (5-100%) over 20 minutes toprovide 4.2 mg (50%) of the product as mono-TFA salt. ¹H NMR (300 MHz,CD₃OD) δ 1.80-1.84 (m, 2H), 2.08-2.02 (m, 2H), 2.23 (s, 3H), 3.07 (bs,4H), 3.30-3.32 (2H, possible overlap with solvent), 3.89 (m, 2H), 4.01(s, 2H), 6.87 (s, 1H), 7.23-7.3 (m, 3H), 7.52-7.60 (m, 3H), 8.01 (d, 2H,J=8 Hz), 8.08 (dd, 1H, J=2.5 Hz), 8.30 (s, 1H), 8.58 (d, 1H, J=5 Hz),8.89 (d, 1H, J=2 Hz), 9.22 (dd, 1H, J=2, 5 Hz), 9.63 (s, 1H); ³¹P (121.4MHz, CD₃OD) δ21.9; MS (m/z) 588 [M+H]⁺.

Example 91-C2-{[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

A solution ofN-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide(20 mg, 0.04 mmol) and2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester (60mg, 0.2 mmol) in 1% Acetic Acid/DMF (1.5 mL) solution was stirred atroom temperature for 7 hours followed by an addition of NaCNBH₃ (30 mg,0.24 mmol). The resulting mixture was stirred for additional 30 min whencompletion of the reaction was observed by LCMS. After evaporation ofsolvent, the residue was taken up in CH₂Cl₂ and then extracted withsaturated aqueous NaHCO₃. The organic extracts were dried in vacuo andthe residue was purified by silica gel chromatography using MeOH—CH₂Cl₂(7%) to afford 8 mg (26%) of the product. ³¹P NMR (121.4 MHz, CDCl₃) δ27.2, 28.6; MS (m/z) 764 [M+H]⁺.

Example 91-D2-{Hydroxy-[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphinoyloxy}-propionicacid

To a solution of2-{[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester (6 mg, 0.008 mmol) in 2:1 acetonitrile/water (0.3 mL)was added 1N NaOH (50 μL, 0.048 mmol). The solution was allowed to stirat room temperature for 1 hour when completion of the reaction wasobserved by LCMS. The reaction was acidified by 1N HCl (50 μL) solutionand purified by RP HPLC using a C18 column with a gradient ofH₂O-Acetonitrile (5-100%) over 20 minutes to provide 2 mg (38%) of theproduct. ¹H NMR (300 MHz, CD₃OD) δ 1.51 (d, 3H, J=7 Hz), 2.04 (m, 2H),2.33 (s, 3H), 2.96 (bs, 4H), 3.31 (m, 2H), 3.4 (bs, 4H), 3.89 (s, 2H),4.88 (1H, possible overlap with solvent), 7.30 (m, 2H), 7.48-7.57 (m,4H), 7.96-7.99 (m, 4H), 8.32 (s, 1H), 8.56 (d, 1H, J=5 Hz), 8.86 (d, 1H,J=2 Hz), 9.10 (dd, 1H, J=2, 5 Hz), 9.59 (s, 1H); ³¹P (121.4 MHz, CD₃OD)δ 20.0; MS (m/z) 660 [M+H]⁺.

Example 92 Preparation of Exemplary Compounds of the Present Invention

Example 92-A6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (222 mg, 0.66 mmol), PPh₃ (260 mg, 0.996 mmol), anddiethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) at 0° C. wasadded a solution of trimethylsilyl ethanol (142 μL, 0.996 mmol) in THF(3 mL). The resulting yellow solution was allowed to warm up to roomtemperature and stirred overnight. The reaction was worked up byconcentrating the solution to dryness and addition of ether and hexanes.Triphenylphosphine oxide was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to provide 248 mgof the desired product as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03(s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m,2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s,3H), 4.25-4.35 (m, 2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H).

Example 92-B[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH₂Cl₂ (10 mL)and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dryice/acetone bath according to the procedure of Smith, D. B. et al., J.Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through thereaction via a gas dispersion tube until the reaction became blue incolor (15 minutes). The ozone line was replaced with a stream ofnitrogen and bubbling continued for another 15 minutes when the bluecolor disappeared. To this solution at −70° C. was added thiourea (75.7mg, 0.994 mmol) in one portion, and the cooling bath was removed. Thereaction was allowed to warm to room temperature and stirred for 15hours. The reaction was worked up by filtration to remove solid thioureaS-dioxide, and then partitioned between CH₂Cl₂ and water. The organiclayer was removed. The aqueous layer was washed with CH₂Cl₂ one moretime and the organic extracts were combined. The organic layer waswashed with aqueous 1N HCl, saturated NaHCO₃ and brine. The organicextracts were dried in vacuo and the residue was purified to by silicagel chromatography to afford 357 mg (75%) of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15(s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s,2H), 9.72 (d, 1H, J=1 Hz).

Example 92-C4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(70 mg, 0.21 mmol) in toluene (2 mL) was heated at 100° C. with2-(triphenylphosphanylidene)-propionaldehyde (72.9 mg, 0.23 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 54 mg (83%) of the desired product as a pale yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16(s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s,2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H).

Example 92-D6-(4-Hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

Example 92-E Phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

To a solution of6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) wasadded 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol)according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12,3889. After 10 minutes, another portion of2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA(35 μL, 0.20 mmol) were added. The reaction was allowed to proceed atroom temperature for an additional hour, after which it was quenched bythe addition of H₂O. The solution was stirred for another 10 minutes andconcentrated in vacuo to a small volume. The product was triturated withdiethyl ether and coevaporated from acetonitrile (4×10 mL) to providethe product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H),1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39(m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹P (121.4MHz, CDCl₃) δ 7.22; MS (m/z) 441 [M−H]⁻.

Example 92-F Phosphoric acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

A solution of phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester(27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at roomtemperature for 3 hours. To the reaction solution was added2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowedto stir for an additional 2 hours at room temperature. The reactionmixture was diluted by addition of H₂O and the solution was stirred for2 more hours when it was concentrated. The residue was dissolved in asolution of 10% TFA/CH₂Cl₂ and stirred at room temperature for 9 hours.The reaction mixture was dried under reduced pressure and the productwas purified by reverse-phase HPLC to provide the desired product as awhite solid. ¹H NMR (300 MHz, CD₃OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47(d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H),5.50-5.61 (m, 1H); ³¹P (121.4 MHz, CD₃OD) δ 0.50; MS (m/z) 357 [M−H]⁻.

Example 92-G6-(2-Hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH₄ inTHF (150 μL, 0.300 mmol). The reaction mixture was stirred at roomtemperature for 1 hour when complete consumption of the startingmaterials was observed by TLC. The reaction mixture was worked up byaddition of an aqueous 1N HCl solution and extraction with EtOAc. Theorganic layer was dried in vacuo and the residue was purified by silicagel chromatography to provide the product. ¹H NMR (300 MHz, CDCl₃) δ0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H),2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H).

Example 92-H{2-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester

A mixture of6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(79 mg, 0.23 mmol) was heated with bromomethylphosphonic aciddiisopropyl ester (120 mg, 0.46 mmol) in the presence of lithiumt-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. Thereaction mixture was purified by reverse-phase HPLC to provide thedesired product. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.13-1.25 (m,2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98 (t, 2H, J=7 Hz),3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H), 4.62-4.74 (m, 2H),5.07 (s, 2H); MS (m/z) 539 [M+Na]⁺.

Example 92-I[2-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-ethoxymethyl]-phosphonicacid

To a solution of{2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL,0.21 mmol) at room temperature. The reaction was allowed to proceed for18 hours when completion of the reaction was indicated by LCMS. Thereaction was quenched by addition of MeOH and concentration. The residuewas purified by reverse-phase HPLC using a C18 column. The collectedproduct was dispensed in a solution of 10% TFA/CH₂Cl₂ to assure completecleavage of the TMSE group. The reaction mixture was lyophilized toprovide the desired product. ¹H NMR (300 MHz, CD₃OD) δ 2.12 (s, 3H),2.98 (t, 2H, J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H); MS(m/z) 331 [M−H]⁻.

Example 92-J6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 h.7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) weresequentially added and the mixture was shaken for 1 h at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 h. The mixture was filtered and thefiltrate was concentrated. The residue was chromatographed on silica gel(0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-oneas an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16 (s,3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68(t, J=7.2 Hz, 1H), 7.71 (brs, 1H).

Example 92-K[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester

A solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(33 mg, 0.097 mmol) in trimethyl phosphite (1.0 mL, 8.5 mmol) was heatedto 100° C. for 1 hour, whereupon complete reaction was indicated byLCMS. The reaction was worked up by removal of the excess of trimethylphosphite under reduced pressure and the residue was purified by silicagel chromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%)of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 1.90 (s, 3H), 2.09 (s,3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz),3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H); MS(m/z) 371 [M+H]⁺.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid (LC-2095-49): To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was addedTMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C.The reaction solution was allowed to warm up to ambient temperature. Thesolution was stirred at room temperature for 2 hours when completion ofthe reaction was observed by LCMS. The reaction was cooled down to 0° C.and quenched with addition of MeOH. The reaction mixture was dried underreduced pressure and the residue was purified by RP HPLC using a C18column with a gradient of H₂O-acetonitrile (5-0%) over 20 minutes toprovide 12.2 mg (73%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 1.95 (s,3H), 2.15 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s,3H), 5.24 (s, 2H), 5.38 (q, 1H, J=7 Hz), 6.87 (br s, 1H); MS (m/z) 341[M−H]⁻.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester: A mixture of7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one(50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem. 2002, 45, 703),diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithiumt-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5h. The reaction was quenched with 1N HCl. The mixture was poured into 5%aqueous lithium chloride, extracted with ethyl acetate, andconcentrated. The residue was purified by chromatography on silica gel,affording[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester as an oil (25 mg, 32%); ¹H NMR (300 MHz, CDCl₃) δ1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58(d, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45(t, J=6.6 Hz, 1H), 7.83 (s, 1H).

Example 92-L[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL,1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL,1.1 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 4 h. The reaction was quenched with methanol at 0° C.,and the resulting mixture was concentrated. The residue was purified bypreparative reverse-phase HPLC to afford, after removal of the solvent,[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid as an oil (17 mg, 83%); ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H),2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97(s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H); MS (m/z) 371 [M−H]⁻.

Example 92-M[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol)was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg,0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed towarm to room temperature and heated to 140° C. for 10 hours. Aftercooling to room temperature the mixture was filtered and extracted withaqueous 1N NaOH solution. The aqueous layer was acidified with aqueous1N HCl and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated to dryness. The residue was purified by reverse-phaseHPLC to provide 18.5 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (major product) as a pale yellow solid and 4.1 mgof[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (minor product) also as a pale yellow solid. Majorproduct: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d,2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s,2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz); ³¹P(121.4 MHz, CD₃OD) δ 17.3; MS (m/z) 449.0 [M+H]⁺, 471.2 [M+Na]⁺. Minorproduct: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d,2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H), 5.50-5.61(m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H); ³¹P (121.4 MHz, CD₃OD) δ16.3; MS (m/z) 525.2 [M+H]⁺, 547.2 [M+Na]⁺.

Example 92-N2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate(47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060mmol). The solution was stirred at room temperature for 1 hour, when anadditional portion of PyBOP (21 mg, 0.040 mmol) was added. The solutionwas stirred for another hour and concentrated. The residue was purifiedby HPLC to provide 7.5 mg of the desired product as a clear oil. ¹H NMR(300 MHz, CD₃OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H,J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78(s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H),4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H),7.33-7.41 (m, 2H); ³¹P (121.4 MHz, CD₃OD) δ 18.9, 20.3; MS (m/z) 549.2[M+H]⁺, 571.3 [M+Na]⁺.

Example 92-O[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

Butyl lithium (1.6 M in hexanes, 1 mL) was added to an equal volume ofTHF at −20° C. A solution of diethyl methylphosphonate (220 mg, 1.45mmol) in THF (1 mL) was then added dropwise and the mixture was stirredfor 30 min. After cooling to 60° C., the solution was transferred via acannula to a vial containing copper (I) iodide (276 mg, 1.45 mmol), andthe resulting mixture was stirred for 1 h at −30° C. A solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(50 mg, 0.15 mmol) in THF (1 mL) was added, and the mixture was allowedto warm to 0° C. for 2 h before saturated aqueous ammonium chloride wasadded. The reaction mixture was acidified with 2 N HCl and extractedwith ethyl acetate. The ethyl acetate extract was concentrated and theresidue was chromatographed on silica gel (40% to 100% ethylacetate/hexanes), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester as an oil (27 mg, contaminated with the startingdiethyl methylphosphonate); ¹H NMR (300 MHz, CDCl₃) δ 1.32 (m, 6H),1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J=7.2, 2H), 3.78(s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J=7.2 Hz, 1H), 7.65 (s,1H).

Example 92-P[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester

A mixture of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL) andwater (1 mL) was stirred at 70° C. for 4 h. After cooling, the reactionsolution was acidified with 2 N HCl, mixed with brine, and extractedwith ethyl acetate/acetonitrle. The organic extract was concentrated andthe residue was purified by preparative reverse-phase HPLC (acetonitrileand 0.1% aqueous CF₃COOH), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester (7 mg, 28%); ¹H NMR (300 MHz, CD₃OD) δ 1.28 (t,J=6.9, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d,J=6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H).

Example 92-Q[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester

To a solution of tetramethylmethylene diphosphonate (102 mg, 0.44 mmol)in THF (2.5 mL) was added a solution of sodium bis(trimethysilyl)amidein THF (1.0 M, 0.44 mL). After stirring for 30 minutes, a solution of4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enal(30 mg, 0.11 mmol, Pankiewicz, et al., J. Med. Chem. 45, 703) in THF(2.5 mL) was added and stirring was continued for an additional 15minutes. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate. Afterevaporation of solvent, the residue was purified by chromatography onsilica gel eluting with ethyl acetate (50% to 100%)/hexanes, affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester (30 mg, 71%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.88(d, 6H), 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65(s, 1H).

Example 92-R[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid

To a solution of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL, 1.71mmol) at 0° C. The mixture was allowed to warm to room temperature andstirred for 1 h. The reaction was quenched with methanol at 0° C., andthe resulting mixture was concentrated. The residue was purified bypreparative reverse-phase HPLC to afford, after removal of the solvent,[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid as a solid (13 mg, 65%); ¹H NMR (300 MHz, CD₃OD) δ 1.91 (s, 3H),2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8(m, 2H), 6.9 (m, 1H).

Example 92-S2-(4-Bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

To a cooled (−78° C.) solution of mycophenolic acid methyl ester (138mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes,a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL)was added and stirring was continued for 10 min. The resulting mixturewas warmed to −30° C. and stored at this temperature for 16 h. Thereaction was quenched with saturated aqueous ammonium chloride. Themixture was extracted with ethyl acetate to give, after evaporation ofthe solvent, a residue which was purified by chromatography on silicagel, eluting with ethyl acetate (0% to 40%)/hexanes, affording2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (150 mg, 78%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H),3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H),5.67 (brs, 2H), 7.67 (s, 1H).

Example 92-T2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

Under a N₂ atmosphere, a solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (490 mg, 1.05 mmol) in trimethyl phosphite (2.5 mL,21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed tocool to room temperature. The reaction mixture was worked up by removalof the solvent in vacuo followed by chromatography using EtOAc-hexanesto provide 460 mg (88%) of the product as an oil. ¹H NMR (300 MHz,CDCl₃) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H,J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H),5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H); ³¹P (121.4 MHz,CDCl₃) δ 30.1; MS (m/z) 497.2 [M+H]⁺, 519.2 [M+Na]⁺.

Example 92-U2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 ofH₂O/MeOH/THF (8 mL) was stirred with LiOH.H₂O (78 mg, 1.86 mmol) atambient temperature for 12 hours. A second batch of LiOH.H₂O (40 mg,0.952 mmol) was added. The reaction mixture was stirred at roomtemperature for another 16 hours, after which no further progress wasobserved. The reaction was quenched by addition of a saturated aqueoussolution of NH₄Cl. The organic layer was removed in vacuo and theproduct was extracted with EtOAc from the aqueous layer, which had beenacidified by addition of 5 drops of 2 N HCl. The product was furtherpurified by chromatography to provide the desired product. ¹H NMR (300MHz, CDCl₃) δ 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d,1-H, J=22 Hz), 2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H,J=7 Hz), 3.72 (d, 6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H,J=6 Hz), 5.36-5.63 (m, 2H); ³¹P (121.4 MHz, CDCl₃) δ 30.5; MS (m/z)481.2 [M−H]⁻.

Example 92-V2-[4-(2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine(60 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). The reaction wasallowed to proceed for 45 minutes when it was completed as judged byLCMS. The reaction mixture was concentrated under reduced pressure andquenched with an aqueous NaOH solution (1 mL). The product was purifiedby reverse-phase HPLC on a C18 column to provide 14.2 mg (60%) of theproduct as a solid. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.081-2.31(m, 4H), 2.16 (s, 3H), 2.45 (d, 1H, J=22 Hz), 2.47 (d, 1H, J=22 Hz),2.55-2.63 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.77 (s, 3H), 5.25 (s, 2H),5.20-5.36 (m, 1H), 5.36-5.56 (m, 2H); ³¹P (121.4 MHz, CD₃OD) δ 25.4; MS(m/z) 453 [M−H]⁻.

Example 92-W2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol)in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33mmol). To this solution was added diethyl azodicarboxylate (230 μL, 1.33mmol) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethylazodicarboxylate (115 μL, 0.665 mmol) were added and the reactionmixture was stirred for another 1 day at room temperature. The reactionwas worked up by removing the solvents in vacuo and purifying theresidue by silica gel chromatography to provide 192 mg (85%) of theproduct as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s,9H), 0.93-0.96 (m, 2H), 1.20-1.29 (m, 2H), 1.78 (s, 3H), 2.01-2.32 (m,4H), 2.17 (s, 3H), 2.51 (d, 1H, J=22 Hz), 2.58 (d, 1H, J=22 Hz),2.50-2.60 (m, 1H), 3.37 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz), 3.76 (s,3H), 4.08 (appt t, 2H, J=8 Hz), 4.30 (appt t, 2H, J=8 Hz), 5.12 (s, 2H),5.15-5.25 (m, 1H), 5.36-5.63 (m, 2H); ³¹P (121.4 MHz, CDCl₃) δ 29.3; MS(m/z) 705.3 [M+Na]⁺.

Example 92-X2-[4-(Hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A mixture of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) intert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. Thesolution was allowed to cool down to room temperature and concentrated.The residue was purified by silica gel column chromatography usingMeOH/CH₂Cl₂ (0-30%) to provide 75 mg of the product as a clear oil. ¹HNMR (300 MHz, CDCl₃) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17(s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H,J=9 Hz), 3.39 (d, 2H, J=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H),4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz),5.33-5.56 (m, 2H), 8.49 (br s, 1H); ³¹P (121.4 MHz, CDCl₃) δ 22.1; MS(m/z) 667.4 [M+Na]⁺.

Example 92-Y2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol), PyBOP (234 mg,0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1hour when complete consumption of the starting materials was observed.The reaction was worked up by addition of saturated aqueous sodiumchloride and ethyl acetate. The organic layer was separated and washedwith 5% aqueous solution of lithium chloride. The organic layer wasdried in vacuo and the residue was purified by silica gel chromatographyusing MeOH—CH₂Cl₂ (0-20%) to provide 57 mg (74%) of the desired productas a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H), 0.05 (s, 9H),0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H,J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m,1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz),3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz),4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H),5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H); ³¹P (121.4MHz, CDCl₃) δ 28.9, 29.9; MS (m/z) 791.4 [M+Na]⁺.

Example 92-Z2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (14 mg, 0.018 mmol) in THF (1 mL)was stirred with a 1M solution of TBAF in THF (55 μL, 0.055 mmol) for 1hour. The reaction mixture was worked up by concentrating the reactionmixture in vacuo and extracting the product from an aqueous 1N HClsolution with EtOAc. The organic layer was washed with brine and dried.The product was purified by silica gel column chromatography EtOH-EtOAc(0-10%). Further purification was performed by dissolving the product inCH₂Cl₂ and passing the compound through a 13 mm Acrodisc syringe filterwith a 0.45 μm Nylon membrane to provide 8 mg (77%) of the product. ¹HNMR (300 MHz, CDCl₃) 0.92 (t, 3H, J=7 Hz), 1.30 (d, 3H, J=8 Hz), 1.79(s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=8 Hz), 2.65 (d,1H, J=22 Hz), 2.68 (d, 1H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.70 and 3.74(d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz),5.20 (s, 2H), 5.27 (br t, 1H, J=7 Hz), 5.33-5.55 (m, 2H), 7.51-7.56 (m,1H), 7.68-7.74 (m, 1H); ³¹P (121.4 MHz, CDCl₃) δ 29.0, 30.1; MS (m/z)569.2 [M+H]⁺, 591.3 [M+Na]⁺.

Example 92-AA2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) intert-butylamine (1 mL, 9.6 mmol) was heated at 65° C. for 16 hours. Thesolution was allowed to cool down to room temperature and concentratedto provide the crude product as an oil. ¹H NMR (300 MHz, CDCl₃) 0.03 (s,9H), 0.04 (s, 9H), 0.86-0.98 (m, 2H), 1.22-1.33 (m, 2H), 1.50 (d, 3H,J=7 Hz), 1.78 (s, 3H), 2.05-2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m,3H), 3.40 (d, 2H, J=7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=9 Hz),4.25-4.33 (m, 2H), 4.75-4.84 (m, 1H), 5.13 (s, 2H), 5.15-5.23 (m, 1H),5.33-5.55 (m, 2H); ³¹P (121.4 MHz, CDCl₃) δ 28.9; MS (m/z) 725.3 [M−H]⁻.

Example 92-AB2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of crude2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammoniumfluoride in THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for2 hours at ambient temperature when an extra amount oftetrabutylammonium fluoride in THF (54 μL, 0.054 mmol) was added. Thereaction was stirred for an additional 16 hours when the reaction wascomplete. The reaction mixture was concentrated in vacuo and the productwas purified by reverse-phase HPLC using a Phenomenex Synergi 5μ HydroRP 80A column (50×21.2 mm) with eluents of H₂O, 0.1% TFA-CH₃CN, 0.1% TFAto provide the product (8.0 mg) as a clear oil. ¹H NMR (300 MHz, CDCl₃)1.51 (d, 3H, J=7 Hz), 1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H),2.49-2.71 (m, 3H), 3.38 (d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H),5.20 (s, 2H), 5.21-5.30 (m, 1H), 5.33-5.63 (m, 2H); ³¹P (121.4 MHz,CDCl₃) δ 27.7, MS (m/z) 525.2 [M−H]⁻.

Example 92-AC2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol), PyBOP (62.4 mg,0.120 mmol) in DMF (1.0 mL) was stirred with L-alanine ethyl esterhydrochloride (18 mg, 0.12 mmol) and DIEA (26 μL, 0.15 mmol) at ambienttemperature for 1 hour when complete consumption of the startingmaterials was observed. The reaction was worked up by addition of wateruntil the reaction solution became cloudy. A minimum amount of DMF wasadded until the reaction became clear again. The reaction mixture wasfiltered through Acrodisc (13 mm syringe filter with a 0.45 μm Nylonmembrane) and purified by reverse-phase HPLC using a Phenomenex Synergi5μ Hydro RP 80A column (50×21.2 mm), eluting with water andacetonitrile. The fractions containing the product were pooled togetherand dried in vacuo to remove the acetonitrile. The aqueous layer wassaturated with sodium chloride and extracted with EtOAc and acetonitrileto provide 7.2 mg of the product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 0.05 (s, 9H), 0.923 (appt t, 2H, J=8 Hz), 1.18-1.31 (m, 5H), 1.41(t, 3H, J=7 Hz), 1.78 (s, 3H), 2.03-2.36 (m, 4H), 2.18 (s, 3H),2.43-2.63 (m, 3H), 3.10-3.30 (m, 1H), 3.40 (d, 2H, J=7 Hz), 3.62 and3.65 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H,J=2, 7 Hz), 4.29 (appt t, 2H, J=8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H),5.33-5.67 (m, 2H); ³¹P (121.4 MHz, CDCl₃) δ 30.4, 31.2; MS (m/z) 790.4[M+Na]⁺.

Example 92-AD2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-{4-[(1-ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (7.2 mg, 9.38 mmol) in THF (1 mL)was added TBAF (40 μL, 1M solution in THF) at room temperature. Thereaction mixture was stirred for 20 minutes when the starting materialswere completely converted to the desired products as observed by LCMS.The reaction mixture was dried in vacuo and re-dissolved in DMF. Theproduct was purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP80A column (50×21.2 mm) with eluents of H₂O—CH₃CN. The fractionscontaining the desired product were pooled and further purified on Dowex50WX8-400 packed on a 4.5 cm×2 cm column to elute the sodium salt atH₂O— MeOH (1:1) to provide 3.2 mg of the desired product. ¹H NMR (300MHz, CD₃OD) δ 1.26 (dd, 3H, J=4, 7 Hz), 1.37 (t, 3H, J=8 Hz), 1.80 (s,3H), 2.00-2.22 (m, 4H), 2.10 (s, 3H), 2.25-2.60 (m, 3H), 3.37 (d, 2H,J=7 Hz), 3.60 and 3.65 (d, 3H, J=11 Hz), 3.74 (s, 3H), 3.83-3.96 (m,1H), 4.18 (q, 2H, J=8 Hz), 5.15 (s, 2H), 5.25-5.42 (m, 2H), 5.55-5.69(m, 1H); ³¹P (121.4 MHz, CD₃OD) δ 33.8, 34.2; MS (m/z) 568.2 [M+H]⁺,590.3 [M+Na]⁺.

Example 92-AE6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-4-methyl-hex-4-enoicacid

To a solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) wasadded TBAF (50 μL, 1M solution in THF) at room temperature. The solutionwas stirred for 16 hours and concentrated. The solution was dried underreduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL).The solution was filtered through Acrodisc (13 mm syringe filter with a0.45 μm Nylon membrane) and purified by RP HPLC using a PhenomenexSynergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H₂O, 0.1%TFA-CH₃CN, 0.1% TFA. The product from the column was subjected to ionexchange chromatography (Sodium salt form of Dowex 50WX8-400) using a2×4.5 cm column eluting with H₂O-MeOH (1:1) to provide 7.5 mg of thedesired product as an oil. ¹H NMR (300 MHz, CDCl₃) 1.80 (s, 3H),2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6Hz), 5.43-5.54 (m, 2H); ³¹P (121.4 MHz, CDCl₃) δ 23.5; MS (m/z) 469.2[M+H]⁺, 491.3 [M+Na]⁺.

Example 92-AF2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

A solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6mmol) in toluene (30 mL) was stirred at reflux for 20 h. The mixture wasconcentrated and chromatographed on silica gel eluting with ethylacetate (60% to 100%)/hexanes, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester as an oil (70 mg, 43%); ¹H NMR (300 MHz, CDCl₃) δ 1.27(m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52 (s,3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H).

Example 92-AG2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) in amixed solvent of THF (6 mL) and water (1 mL) was stirred at roomtemperature for 6 h. The organic solvent was removed and the residue waspartitioned between ethyl acetate and 5% aqueous sodium bicarbonate. Theaqueous layer was acidified with 2 N HCl and extracted with ethylacetate. The ethyl acetate extract was concentrated, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid as an oil (30 mg, 100%); ¹H NMR (300 MHz, CDCl₃) δ 1.27 (m, 6H),1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08(m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45(m, 2H).

Example 92-AH2-[4-(Ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) ina mixed solvent of methanol (3 mL) and water (1 mL) was stirred at 70°C. for 2 h. The organic solvent was removed and then acidified with 2NHCl and extracted with ethyl acetate/acetonitrile. The organic extractwas concentrated and the residue was purified by preparativereverse-phase HPLC (acetonitrile and 0.1% aqueous CF₃COOH), affording22-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid as an oil (15 mg, 89%); ¹H NMR (300 MHz, CD₃OD) δ 1.25 (t, J=6.9Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s,3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H).

Example 93 Preparation of Exemplary Compounds of the Present Invention

Compounds such as 1 can be made according to the general route outlinedin Scheme 1, with an example depicted in Scheme 2.

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound1.1.1, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., Protective groups in organicsynthesis, Wiley-Interscience, 1999. Compound 1.1.1 is then treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate 1 after deprotection of the BOC groupusing trifluoroacetic acid (TFA).

Compounds such as 2 and 3 can be made according to the general routeoutlined in Scheme 3, with an example depicted in Scheme 4.

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound1.1, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., Protective groups in organicsynthesis, Wiley-Interscience, 1999. Subsequent protection of theprimary alcohol using a TBS group can be achieved using TBSCl andimidazole in solvents such as CH₂Cl₂ as described in Greene, T.Protective groups in organic synthesis, Wiley-Interscience, 1999 toprovide compound 1.1. Compound 1.1 is then treated in a solvent such astetrahydrofuran or dimethylformamide with a base such as sodium hydride.When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding amixture of the desired phosphonate diester 2 and 3 after deprotection ofthe BOC group using trifluoroacetic acid (TFA). Compounds 2 and 3 can bealso prepared via a more complicated 2′ OH protected analog of 1.1followed by alkylation using the diethyl phosphonomethyltriflate toprovide compound 2 exclusively. Compound 3 can also be prepared byinstallation of a different protecting group at the 3′ OH position,followed by deprotection of 2′ OH and alkylation with diethylphosphonomethyltriflate at the 2′ center followed by globaldeprotection.

Example 94 Preparation of Exemplary Compounds of the Present InventionIV. Parent Molecule:

General Target Structures:

A synthetic scheme towards a specific target I is outlined below:

Recommended procedure for O-alkylation: mix the phenol and Cs₂CO₃ (ca.1:1.2) in DMF and stir well for 30 min at 0° C. Add the triflate (1.2eq.). The reaction should be complete within an hour.

Experimental for the trifluoromethanesulfonyloxymethylphosphonate willbe provided separately.

Additional Compounds The following target II will be prepared after aninitial biological evaluation of the target I.

Reference for camptothecin-7-aldehyde: Chem. Pharm. Bull. 1991, 39,2574. Reference for reactions of Wittig ylides with the camptothecinaldehyde: J. Med. Chem. 2000, 43, 3963.

Example 95 Preparation of Exemplary Compounds of the Present InventionV. Parent Molecule:

General Target Structures:

A synthetic scheme towards a specific target I is outlined below:

Reference of reductive amination of anthracyclines: J. Med. Chem. 1998,41, 965. Experimental for the aldehyde intermediate from the allylphosphonate will be provided.

Additional Compounds The following two targets II and III will beprepared after an initial biological evaluation of the target I.

Reference for N-acylation of anthracyclines: J. Med. Chem. 1980, 23,1166

Example 96 Preparation of Exemplary Compounds of the Present InventionParent Molecule:

Target Classes:

A synthetic scheme towards specific targets I and II is outlined below.

Reference for synthesis of target I: Org. Pro. Res. Dev. web publicationwill be provided.

Additional Compounds The following targets III and IV will be preparedafter an initial biological evaluation of the targets I and II.

Mycophenolate

Representative compounds of the invention having the following formulaecan be prepared as described in Examples 201-204.

For example, three regions of mycophenolate mofetil can be utilized forthe attachment of the phosphonate prodrug as demonstrated by compoundsD, E, and G shown above. Also, the carboxylic acid can be replaced witha phosphonic acid as in compound F.

Example 201 Preparation of Representative Compounds of Formula 204

Representative compounds of the invention can be prepared as illustratedabove. The morpholino ethyl moiety can serve as a prodrug functionalityto improve bioavailability and can be replaced with the phosphonateprodrug handle as shown above. Mycophenolic acid is commerciallyavailable, e.g., from Sigma Chemical Company, St. Louis, Mo. Activationof the carboxylic acid 201.1 in the presence of the free phenol,followed by addition of an alcohol carrying the phosphonate group,results in the formation of the desired product 201.3 (U.S. Pat. No.4,786,637). A specific compound of the invention can be prepared asfollows.

Mycophenolic acid 201.1 is dissolved in dichloromethane. Thionylchloride is added followed by a catalytic amount of DMF. The reactionmixture is stirred at room temperature for 3 hours, after which thevolatile components are removed under vacuum. The phosphonate-alcohol isdissolved in dichloromethane and chilled to about 4° C. on an ice bath.The mycophenolic acid chloride 201.2 is dissolved in dichloromethane andadded to the chilled solution. After stirring for 90 minutes at about 4°C., the reaction mixture is washed with water and then with aqueoussodium bicarbonate. The organic solution is dried and evaporated toyield the phosphonate 201.3.

Example 202 Preparation of Representative Compounds of Formula 207

Representative compounds of the invention can be prepared as illustratedabove. The C-4 phenol position provides a reactive handle for furtheranalogs as illustrated above. Once the carboxylic acid of 202.1 isblocked by morpholino ethyl, such as in compound 202.2 the phenol can bealkylated under basic conditions. Bases such as pyridine, potassiumcarbonate, or triethylamine are utilized. Leaving groups such astrifluoromethylsulfonate, mesylate, bromide, or iodide are attached tothe phosphonate prodrug subunit and reacted, in the presence of base,with compound 202.2. Compound 2023 can either be used directly, or inthe form of a salt, compound 202.4. Among the large number of salts thatcan be prepared, chloride and bisulfate salts are one particularembodiment of the invention. A specific compound of the invention can beprepared as follows.

Compound 202.5 is prepared similar to compound 201.2 (described inExample 201). A solution of morpholino ethanol in dichloromethane iscooled to about 4° C. The mycophenolic acid chloride 202.5 is dissolvedin dichloromethane and added to the cooled solution. Stirring thissolution for about 90 minutes gives compound 202.2. The reaction mixtureis washed with water and dried with sodium sulfate. Removal of thesolvent provides isolated compound 202.2. Alkylation at the phenolicposition of 202.2 is achieved by suspending the compound in pyridine.Triflate 202.6 is added to the solution and the mixture is stirred atroom temperature for about 90 minutes. The reaction mixture is pouredinto water and the product is extracted with ethyl acetate. Removal ofthe organic layer provides compound 202.7. Hydrochloride salt of 202.7can optionally be prepared. Compound 202.7 is dissolved in isopropanoland the solution is added to a mixture of hydrogen chloride inisopropanol. The hydrochloride salt 202.8 is collected by filtration anddried under vacuum.

Example 203 Preparation of Representative Compounds of Formula 205

Representative compounds of the invention can be prepared as illustratedabove. The carboxylic acid of mycophenolic acid can be replaced with aphosphonic acid that may also serves as a prodrug handle. In order toremove the carboxylic acid containing side chain, the acid chloride202.5 (prepared in Example 202) is converted to ester 203.1. Protectionof the phenol with a silyl group, followed by dihydroxylation andcleavage of the diol generates aldehyde 203.3 (Pankiewicz, et al., J.Med. Chem., 2002, 45, 703), (Patterson et al., U.S. Pat. No. 5,444,072)(Example 20). A Wittig reaction with ylide 203.4 carrying anappropriately protected phosphonate provides the desired compound 203.5.Final deprotection yields compound 203.6. A specific compound of theinvention can be prepared as follows.

Mycophenolate ester 203.8 can simply be prepared by stirring the acidchloride 203.7 with MeOH. Then, the phenol position of mycophenolateester is protected by a silyl group such as TBS to provide compound203.9. Once the phenol position is protected, dihydroxylation usingosmium tetraoxide followed by periodinate cleavage provides aldehyde203.10. Aldehyde 203.10 and excess of the ylide 203.11 are heated inbenzene at reflux for about 24 hours. The reaction mixture isconcentrated and the residue is purified by column chromatography toprovide olefin 203.12 (Pankiewics et al., J. Med. Chem., 2002, 45, 703).A final deprotection using HF-pyridine yields the final product 203.13.

Example 204 Preparation of Representative Compounds of Formula 208

Representative compounds of the invention can be prepared as illustratedabove. Another attachement point of the compound can be unmasked afterdemethylation of mycophenolate ester 204.2 as illustrated above. Forthis purpose, the 4-OH needs to be masked with a protecting group (P)such as a silyl group. Once the 6-MeO is demethylated and alkylated, theprotecting group at position 4 is removed to reveal the final product204.4. The morphonyl ethanol group is installed early and carriedthrough the alkylation steps. A different protecting group may beinstalled initially and removed later. In such the latter type ofsynthesis, the last step is the formation of the morpholinoethyl esterprodrug. A specific compound of the invention can be prepared asdescribed below.

Phenol 204.5 is protected with TBS group in CH₂Cl₂ using imidazole asbase to yield 204.6. Demethylation is performed using thiolatenucleophiles to generate compound 204.7. A variety of other methods arealso available in literature as described in Protective Groups inOrganic Synthesis by Greene and Wuts. Alklation of the 6-OH using atriflate of the phosphonate proceeds well using K₂CO₃ or TEA to provide204.8. Final deprotection to remove the TBS group provides product204.9.

Example 251 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedabove.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester

A mixture of7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703),diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithiumt-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5hours. The reaction was quenched with 1N HCl. The mixture was pouredinto 5% aqueous lithium chloride, extracted with ethyl acetate, andconcentrated. The residue was purified by chromatography on silica gel,affording[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 32%); ¹H NMR (300 MHz, CDCl₃) δ1.25(m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d,2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t,J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL,1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL,1.1 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 4 hours. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid 1C as an oil (17 mg, 83%); ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H),2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97(s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H) and[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester 1D as an oil (2 mg, 7%); ¹H NMR (300 MHz,CD₃OD)

1.23 (d, 6H), 1.81 (s, 3H), 2.08 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50(d, 2H), 3.77 (s, 3H), 3.90 (s, 2H), 4.50 (m, 1H), 5.20 (s, 2H), 5.47(t, J=6.6 Hz, 1H) ppm.

Example 252 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester

To a solution of tetramethylmethylene diphosphonate (102 mg, 0.44 mmol)in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.44 mL). After stirring for 30 minutes,a solution of4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enal2A (30 mg, 0.11 mmol, Pankiewicz et al., J. Med. Chem., 45, 703) in THF(2.5 mL) was added, and stirring was continued for an additional 15minutes. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate. Afterevaporation of solvent, the residue was purified by chromatography onsilica gel eluting with ethyl acetate (50% to 100%)/hexanes, affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (30 mg, 71%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.88(d, 6H), 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid

To a solution of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL,1.71 mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL,1.71 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 1 hour. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid 2C as a solid (13 mg, 65%); ¹H NMR (300 MHz, CD₃OD) δ 1.91 (s, 3H),2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8(m, 2H), 6.9 (m, 1H) ppm.

Example 253 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-oneIA (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) weresequentially added and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour. The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B as an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16(s, 3H), 3.44 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s,2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

n-Butyl lithium (1.6 M in hexanes, 1 mL) was added to an equal volume ofTHF at −20° C. A solution of diethyl methylphosphonate (220 mg, 1.45mmol) in THF (1 mL) was then added dropwise and the solution was stirredfor 30 minutes. After cooling at 60° C., the solution was transferredvia a cannula to a vial containing copper (1) iodide (276 mg, 1.45mmol), and the resulting mixture was stirred for 1 hour at −30° C. Asolution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B (50 mg, 0.15 mmol) in THF (1 mL) was added and the mixture wasallowed to warm to 0° C. for 2 hours before saturated aqueous ammoniumchloride was added. The reaction mixture was acidified with 2 N HCl andextracted with ethyl acetate. The ethyl acetate extract was concentratedand the residue was chromatographed on silica gel (40% to 100% ethylacetate/hexanes), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C as an oil (27 mg, contaminated with the startingdiethyl methylphosphonate); ¹H NMR (300 MHz, CDCl₃) δ 1.32 (m, 6H),1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J=7.2 Hz, 2H),3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J=7.2 Hz, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester

A mixture of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL)and water (1 mL) was stirred at 70° C. for 4 hours. After cooling, thereaction solution was acidified with 2 N HCl, mixed with brine, andextracted with ethyl acetate/acetonitrle. The organic extract wasconcentrated and the residue was purified by preparative reverse-phaseHPLC (acetonitrile and 0.1% aqueous CF₃COOH), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester 3D (7 mg, 28%); ¹H NMR (300 MHz, CD₃OD) δ 1.28 (t,J=6.9 Hz, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d,J=6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{5-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-sobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (50.5 μL, 0.39 mmol) followed by 2,6-lutidine (45.3 μL,0.39 mmol). The reaction was allowed to proceed for one hour when it wascomplete, as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC. The fraction containing the desired product wasconcentrated and treated with 10% TFA/DCM for 5 minutes. Afterconcentration, the residue was purified by preparative reverse-phaseHPLC to provide 7 mg (50%) of[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid as a solid. ¹H NMR (300 MHz, CD₃OD) δ 1.66-1.78 (m, 5H), 2.10 (s,3H), 2.16-2.22 (m, 2H), 3.34 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s,2H), 5.20 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 31.57 ppm; MS(m/z) 355 [M−H]⁻, 357 [M+H]⁺.

Example 254 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(4-Bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

To a cooled (−78° C.) solution of mycophenolic acid methyl ester 4A (138mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes,a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL)was added and stirring was continued for 10 minutes. The resultingmixture was warmed to −30° C. and stored at this temperature for 16hours. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate to give, afterevaporation of the solvent, a residue that was purified bychromatography on silica gel eluting with ethyl acetate (0% to40%)/hexanes, affording2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (150 mg, 78%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H),3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H),5.67 (brs, 2H), 7.67 (s, 1H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

A solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg,3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. Themixture was concentrated and chromatographed on silica gel eluting withethyl acetate (60% to 100%)/hexanes, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C as an oil (70 mg, 43%); ¹H NMR (300 MHz, CDCl₃) δ1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52(s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg)in a mixture of THF (6 mL) and water (1 mL) was stirred at roomtemperature for 6 hours. The organic solvent was removed and the residuewas partitioned between ethyl acetate and 5% aqueous sodium bicarbonate.The aqueous layer was acidified with 2 N HCl and extracted with ethylacetate. The ethyl acetate extract was concentrated, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4D as an oil (30 mg, 100%); ¹H NMR (300 MHz, CDCl₃) δ 1.27 (m, 6H),1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08(m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45(m, 2H) ppm.

2-[4-(Ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg)in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C.for 2 hours. The organic solvent was evaporated and the residueacidified with 2N HCl and extracted with ethyl acetate/acetonitrile. Theorganic extract was concentrated, and the residue was purified bypreparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF₃COOH),affording2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4E as an oil (15 mg, 89%); ¹H NMR (300 MHz, CD₃OD) δ 1.25 (t, J=6.9Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s,3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

Under a N₂ atmosphere, a solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL,21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed tocool to room temperature. The reaction mixture was worked up by removalof the solvent in vacuo followed by chromatography using EtOAc-hexanesto provide 460 mg (88%) of the product as an oil. ¹H NMR (300 MHz,CDCl₃) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H,J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H),5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 30.1 ppm; MS (m/z) 497.2 [M+H]⁺, 519.2 [M+Na]⁺.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 of H₂O,MeOH, THF (8 mL) was stirred with LiOH.H₂O (78 mg, 1.86 mmol) at ambienttemperature for 12 hours. A second batch of LiOH.H₂O (40 mg, 0.952 mmol)was added. The reaction mixture was stirred at room temperature foranother 16 hours, after which no further progress was observed. Thereaction was quenched by addition of a saturated aqueous solution ofNH₄Cl. The organic layer was removed in vacuo and the product wasextracted with EtOAc from the aqueous layer, which had been acidified byaddition of 5 drops of 2 N HCl. The product was further purified bychromatography to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=22 Hz),2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.72 (d,6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36-5.63(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.5 ppm; MS (m/z) 481.2 [M−H]⁻.

2-[4-(2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine(60 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). The reaction wasallowed to proceed for 45 minutes when it was completed as judged byLCMS. The reaction mixture was concentrated under reduced pressure andquenched with an aqueous NaOH solution (1 mL). The product was purifiedby RP HPLC (using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA) to provide 14.2 mg (60%) of the product as asolid. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16(s, 3H), 2.45 (d, 1H, J=22 Hz), 2.47 (d, 1H, J=22 Hz), 2.55-2.63 (m,1H), 3.38 (d, 2H, J=7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20-5.36 (m,1H), 5.36-5.56 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 25.4 ppm; MS (m/z)453 [M−H]⁻.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol)in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33mmol). To this solution was added diethyl azodicarboxylate (230 μL, 1.33mmol) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethylazodicarboxylate (115 μL, 0.665 mmol) were added and the reactionmixture was stirred for another 1 day at room temperature. The reactionwas worked up by removing the solvents in vacuo and purifying theresidue by silica gel chromatography to provide 192 mg (85%) of theproduct as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s,9H), 0.93-0.96 (m, 2H), 1.20-1.29 (m, 2H), 1.78 (s, 3H), 2.01-2.32 (m,4H), 2.17 (s, 3H), 2.51 (d, 1H, J=22 Hz), 2.58 (d, 1H, J=22 Hz),2.50-2.60 (m, 1H), 3.37 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz), 3.76 (s,3H), 4.08 (appt t, 2H, J=8 Hz), 4.30 (appt t, 2H, J=8 Hz), 5.12 (s, 2H),5.15-5.25 (m, 1H), 5.36-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.3ppm; MS (m/z) 705.3 [M+Na]⁺.

2-[4-(Hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A mixture of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) intert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. Thesolution was allowed to cool to room temperature and concentrated. Theresidue was purified by silica gel column chromatography usingMeOH/CH₂Cl₂ (0-30%) to provide 75 mg of the product as a clear oil. ¹HNMR (300 MHz, CDCl₃) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17(s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H,J=9 Hz), 3.39 (d, 2H, J=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H),4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz),5.33-5.56 (m, 2H), 8.49 (br s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.1ppm; MS (m/z) 667.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) and PyBOP (234mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate(53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperaturefor 1 hour, when complete consumption of the starting materials wasobserved. The reaction was worked up by addition of saturated aqueoussodium chloride and ethyl acetate. The organic layer was separated andwashed with 5% aqueous solution of lithium chloride. The organic layerwas dried in vacuo and the residue was purified by silica gelchromatography using MeOH—CH₂Cl₂ (0-20%) to provide 57 mg (74%) of thedesired product as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H),0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s,3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz),3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07(appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9, 29.9 ppm; MS (m/z) 791.4[M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (14 mg, 0.018 mmol) in THF (1 mL)was stirred with a 1M solution of TBAF in THF (55 μL, 0.055 mmol) for 1hour. The reaction mixture was concentrated, acidified with 1N HCl andextracted with EtOAc. The organic layer was washed with brine and dried.The product was purified by silica gel column chromatography EtOH-EtOAc(0-10%). Further purification was performed by dissolving the product inCH₂Cl₂ and passing the compound through a 13 mm Acrodisc syringe filterwith a 0.45 μm Nylon membrane to provide 8 mg (77%) of the product. ¹HNMR (300 MHz, CDCl₃) δ 0.92 (t, 3H, J=7 Hz), 1.30 (d, 3H, J=8 Hz), 1.79(s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=8 Hz), 2.65 (d,1H, J=22 Hz), 2.68 (d, 1H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.70 and 3.74(d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz),5.20 (s, 2H), 5.27 (br t, 1H, J=7 Hz), 5.33-5.55 (m, 2H), 7.51-7.56 (m,1H), 7.68-7.74 (m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.0, 30.1 ppm; MS(m/z) 569.2 [M+H]⁺, 591.3 [M+Na]⁺.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) intert-butylamine (1 mL, 9.6 mmol) was heated at 65° C. for 16 hours. Thesolution was allowed to cool to room temperature and concentrated toprovide the crude product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 0.04 (s, 9H), 0.86-0.98 (m, 2H), 1.22-1.33 (m, 2H), 1.50 (d, 3H,J=7 Hz), 1.78 (s, 3H), 2.05-2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m,3H), 3.40 (d, 2H, J=7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=9 Hz),4.25-4.33 (m, 2H), 4.75-4.84 (m, 1H), 5.13 (s, 2H), 5.15-5.23 (m, 1H),5.33-5.55 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9 ppm; MS (m/z) 725.3[M−H]⁻.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of crude2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammoniumfluoride in THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for2 hours at ambient temperature, when more tetrabutylammonium fluoride inTHF (54 μL, 0.054 mmol) was added. The reaction was stirred for anadditional 16 hours, by which time the reaction was complete. Thereaction mixture was concentrated in vacuo and the product was purifiedby RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2mm) with eluents of H₂O, 0.1% TFA-CH₃CN, 0.1% TFA to provide the product(8.0 mg) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.51 (d, 3H, J=7 Hz),1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38(d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21-5.30(m, 1H), 5.33-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.7 ppm; MS(m/z) 525.2 [M−H]⁻.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol), PyBOP (62.4 mg,0.120 mmol) in DMF (1.0 mL) was stirred with L-alanine ethyl esterhydrochloride (18 mg, 0.12 mmol) and DIEA (26 μL, 0.15 mmol) at ambienttemperature for 1 hour, when complete consumption of the startingmaterials was observed. The reaction was worked up by addition of wateruntil the reaction solution became cloudy. DMF was added dropwise untilthe mixture became clear again. The reaction mixture was filteredthrough Acrodisc (13 mm syringe filter with a 0.45 μm Nylon membrane)and purified by RP HPLC using a Phenomenex Synergi 5 p Hydro RP 80Acolumn (50×21.2 mm), eluting with water and acetonitrile. The fractionscontaining the product were pooled together and concentrated in vacuo toremove the acetonitrile. The remaining solution was saturated withsodium chloride and extracted with EtOAc and acetonitrile to provide 7.2mg of the product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s, 9H),0.923 (appt t, 2H, J=8 Hz), 1.18-1.31 (m, 5H), 1.41 (t, 3H, J=7 Hz),1.78 (s, 3H), 2.03-2.36 (m, 4H), 2.18 (s, 3H), 2.43-2.63 (m, 3H),3.10-3.30 (m, 1H), 3.40 (d, 2H, J=7 Hz), 3.62 and 3.65 (d, 3H, J=11 Hz),3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H, J=2, 7 Hz), 4.29 (appt t,2H, J=8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33-5.67 (m, 2H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 30.4, 31.2 ppm; MS (m/z) 790.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-{4-[(1-ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (7.2 mg, 9.38 mmol) in THF (1 mL)was added TBAF (40 μL, 1M solution in THF) at room temperature. Thereaction mixture was stirred for 20 minutes, when the starting materialwas completely converted to the desired product as judged by LCMS. Thereaction mixture was dried in vacuo and re-dissolved in DMF. The productwas purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm) with eluents of H₂O—CH₃CN. The fractions containingthe desired product were pooled and further purified on Dowex 50WX8-400packed on a 4.5 cm×2 cm column to elute the sodium salt at H₂O— MeOH(1:1), providing 3.2 mg of the desired product. ¹H NMR (300 MHz, CD₃OD)δ 1.26 (dd, 3H, J=4, 7 Hz), 1.37 (t, 3H, J=8 Hz), 1.80 (s, 3H),2.00-2.22 (m, 4H), 2.10 (s, 3H), 2.25-2.60 (m, 3H), 3.37 (d, 2H, J=7Hz), 3.60 and 3.65 (d, 3H, J=11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H),4.18 (q, 2H, J=8 Hz), 5.15 (s, 2H), 5.25-5.42 (m, 2H), 5.55-5.69 (m, 1H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 33.8, 34.2 ppm; MS (m/z) 568.2 [M+H]⁺,590.3 [M+Na]⁺.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-4-methyl-hex-4-enoicacid

To a solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) wasadded TBAF (50 μL, 1M solution in THF) at room temperature. The solutionwas stirred for 16 hours and concentrated. The solution was dried underreduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL).The solution was filtered through Acrodisc (13 mm syringe filter with a0.45 μm Nylon membrane) and purified by RP HPLC using a PhenomenexSynergi 5 μl Hydro RP 80A column (50×21.2 mm) with eluents of H₂O, 0.1%TFA-CH₃CN, 0.1% TFA. The product from the column was subjected to ionexchange chromatography (Sodium salt form of Dowex 50WX8-400) using a2×4.5 cm column eluting with H₂O-MeOH (1:1) to provide 7.5 mg of thedesired product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 1.80 (s, 3H),2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6Hz), 5.43-5.54 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.5 ppm; MS (m/z)469.2 [M+H]⁺, 491.3 [M+Na]⁺.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL)at 0° C. was added a solution of 2-trimethylsilylethanol (142 μL, 0.996mmol) in THF (3 mL). The resulting yellow solution was allowed to warmto room temperature and stirred overnight. The reaction was concentratedto dryness and ether and hexanes were added. Triphenylphosphine oxidewas removed by filtration and the filtrate was concentrated and purifiedby silica gel chromatography to provide 248 mg of the desired product asa colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.18-1.30 (m,2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H),3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H),5.13 (s, 2H), 5.12-5.22 (m, 1H) ppm.

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH₂Cl₂ (10 mL)and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dryice/acetone bath according to the procedure of Smith, D. B. et al., J.Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through thereaction via a gas dispersion tube until the reaction became blue incolor (15 minutes). The ozone line was replaced with a stream ofnitrogen and bubbling continued for another 15 minutes, by which timethe blue color had disappeared. To this solution, thiourea (75.7 mg,0.994 mmol) was added in one portion at −70° C., and the cooling bathwas removed. The reaction was allowed to warm to room temperature andstirred for 15 hours. The reaction was worked up by filtration to removesolid thiourea S-dioxide, and then partitioned between CH₂Cl₂ and water.The organic layer was removed. The aqueous layer was washed with CH₂Cl₂one more time, and the organic extracts were combined. The organic layerwas washed with aqueous 1N HCl, saturated NaHCO₃ and brine. The organicextracts were dried in vacuo and the residue was purified to by silicagel chromatography to afford 357 mg (75%) of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15(s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s,2H), 9.72 (d, 1H, J=1 Hz) ppm.

4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(70 mg, 0.21 mmol) in toluene (2 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-propionaldehyde (72.9 mg, 0.23 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 54 mg (83%) of the desired product as a pale yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16(s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s,2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H) ppm.

6-(4-Hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.

6-(2-Hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH₄ inTHF (150 μL, 0.300 mmol). The reaction mixture was stirred at roomtemperature for 1 hour when complete consumption of the startingmaterials was observed by TLC. The reaction mixture was worked up byaddition of an aqueous 1N HCl solution and extraction with EtOAc. Theorganic layer was dried in vacuo and the residue was purified by silicagel chromatography to provide the product. ¹H NMR (300 MHz, CDCl₃) δ0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H),2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H) ppm.

{2-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester

A mixture of6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(79 mg, 0.23 mmol) was heated with bromomethylphosphonic aciddiisopropyl ester (120 mg, 0.46 mmol) in the presence of lithiumt-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. Thereaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueousCF₃COOH) to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.13-1.25 (m, 2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98(t, 2H, J=7 Hz), 3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H),4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS (m/z) 539 [M+Na]⁺.

Example 255 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-ethoxymethyl]-phosphonicacid

To a solution of{2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL,0.21 mmol) at room temperature. The reaction was allowed to proceed for18 hours when completion of the reaction was indicated by LCMS. Thereaction was quenched by addition of MeOH and concentration. The residuewas purified by RP-HPLC using a C18 column. The collected product wasdissolved in a solution of 10% TFA/CH₂Cl₂ to assure completedeprotection. The reaction mixture was lyophilized to provide thedesired product. ¹H NMR (300 MHz, CD₃OD) δ 2.12 (s, 3H), 2.98 (t, 2H,J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H) ppm; MS (m/z) 331[M−H]⁻.

Example 256 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-oneas an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16 (s,3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68(t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester

A solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(33 mg, 0.097 mmol) in trimethylphosphite (1.0 mL, 8.5 mmol) was heatedto 100° C. for 1 hour, whereupon complete reaction was indicated byLCMS. The reaction was worked up by removal of the excess reagent underreduced pressure and the residue was purified by silica gelchromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 1.90 (s, 3H), 2.09 (s,3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz),3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H) ppm;MS (m/z) 371 [M+H]⁺.

Example 257 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was addedTMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C.The reaction solution was allowed to warm to room temperature andstirred for 2 hours when completion of the reaction was observed byLCMS. The reaction was cooled to 0° C. and quenched by the addition ofMeOH. The reaction mixture was concentrated under reduced pressure andthe residue was purified by RP HPLC using a C18 column with a gradientof H₂O-acetonitrile (5-0%) over 20 minutes to provide 12.2 mg (73%) ofthe product. ¹H NMR (300 MHz, CD₃OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48(d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38(q, 1H, J=7 Hz), 6.87 (br s, 1H) ppm; MS (m/z) 341 [M−H]⁻.

Example 258 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol)was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg,0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed towarm to room temperature and heated to 140° C. for 10 hours. Aftercooling to room temperature the mixture was filtered and extracted withaqueous 1N NaOH solution. The aqueous layer was acidified with aqueous1N HCl and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated to dryness. The residue was purified by RP HPLC toprovide 18.5 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (major product, Example 8) as a pale yellow solidand 4.1 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (minor product) also as a pale yellow solid. Majorproduct: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d,2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s,2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm;³¹P (121.4 MHz, CD₃OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]⁺, 471.2 [M+Na]⁺.Minor product: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.15 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H),5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; ³¹P (121.4MHz, CD₃OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]⁺, 547.2 [M+Na]⁺.

Example 259 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate(47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060mmol). The solution was stirred at room temperature for 1 hour, when anadditional portion of PyBOP (21 mg, 0.040 mmol) was added. The solutionwas stirred for another hour and concentrated. The residue was purifiedby HPLC to provide 7.5 mg of the desired product as a clear oil. ¹H NMR(300 MHz, CD₃OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H,J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78(s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H),4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H),7.33-7.41 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 18.9, 20.3 ppm(diastereomers at phosphorus); MS (m/z) 549.2 [M+H]⁺, 571.3 [M+Na]⁺.

Example 260 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (20 mg, 0.045 mmol) and L-alanine ethyl esterhydrochloride (68.5 mg, 0.45 mmol) in pyridine (1.0 mL) was added PyBOP(70 mg, 0.14 mmol). After stirring overnight, the mixture wasconcentrated and the residue purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 3.6 mg ofthe product as a colorless gel. ¹H NMR (300 MHz, CD₃OD) δ 1.17-1.3 (m,6H), 1.8-1.9 (m, 3H), 2.16 (s, 3H), 3.17 (m, 1H), 3.47 (d, 2H), 3.72-3.8(m, 5H), 3.92-4.2 (m, 4H), 5.25 (s, 2H), 5.54 (m, 1H), 7.18 (m, 3H),7.33 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 24.1, 25.0 ppm (diastereomersat phosphorus); MS (m/z) 546.2 [M−H]⁺.

Example 261 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monomethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (53 mg, 0.1 mmol) in methanol (0.5 mL) was added anaqueous solution of 1N NaOH (300 μL). After stirring overnight, themixture was concentrated and the residue purified by RP HPLC using a C18column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 5 mg of the product as a colorless gel, together with thephosphonic acid monophenyl ester (7 mg) and the phosphonic acid dimethylester (14.5 mg). ¹H NMR (300 MHz, CD₃OD) δ 1.84 (s, 3H), 2.16 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.6 (d, 2H, J=12 Hz), 3.75 (d, 3H, J=11 Hz), 3.79(s, 3H), 3.94 (s, 2H), 5.26 (s, 2H), 5.53 (t, 1H, J=7 Hz) ppm; ³¹P(121.4 MHz, CD₃OD) δ 21.5 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1 [M+H]⁺.

Example 262 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl esteroxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg,0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) atroom temperature. The solution was stirred for 2 days when it wasquenched by addition of saturated aqueous sodium bicarbonate solutionand EtOAc. The organic layer was separated and concentrated underreduced pressure. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115mg (96%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s,9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s,3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54(s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13(s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 27.8 ppm; MS (m/z) 542.3 [M+H]⁺, 564.2 [M+Na]⁺.

{2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 μL, 0.55 mmol), and2,6-lutidine (64 μL, 0.55 mmol) was stirred in CH₂Cl₂ (1 mL) and DMF(0.5 mL) for 1 hour at ambient temperature. The reaction mixture waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 7.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16(s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.57 (s, 2H), 3.81 (s,3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃OD) δ20.2 ppm; ¹⁹F NMR (282.6 MHz, CD₃OD) δ −74.0 ppm; MS (m/z) 386.3 [M+H]⁺.

Example 263 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (45 mg, 0.092 mmol) in CH₂Cl₂ (0.5 mL) was stirredwith methanesulfonyl chloride (21 μL, 0.28 mmol) and pyridine (45 μL,0.55 mmol) at ambient temperature overnight. The reaction was quenchedby addition of 2 drops of water. The reaction mixture was concentratedand purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 36 mg of the product (63%) as aclear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H),1.29 (t, 6H, J=7 Hz), 1.85 (s, 3H), 2.00-2.13 (m, 2H), 2.19 (s, 3H),2.85 (s, 3H), 3.32-3.43 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.69 (s, 2H),3.79 (s, 3H), 4.05 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H),5.45 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃Cl) δ 27.5 ppm; MS (m/z)642.2 [M+Na]⁺.

(2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-methanesulfonyl-amino}-ethyl)-phosphonicacid

A solution of[2-(methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) wasstirred with TMSBr (38 μL, 0.29 mmol) and 2,6-lutidine (34 μL, 0.29mmol) for 2 hours at room temperature. The reaction was worked up byaddition of EtOAc and aqueous 1N HCl. The organic layer was washed withbrine and the solvent was removed in vacuo. The residue was suspended ina solution of 10% TFA-CH₂Cl₂ for 10 minutes before it was dried toprovide 9.9 mg of the desired product (73%) as a white solid. ¹H NMR(300 MHz, DMSO-d6) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87(s, 3H), 3.24-3.35 (m, 2H), 3.39 (d, 2H, J=7 Hz), 3.65 (s, 2H), 3.75 (s,3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; ³¹P (121.4 MHz, DMSO-d6) δ21.4 ppm; MS (m/z) 464.1 [M+H]⁺.

Example 264 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL) was addedacetic anhydride (0.5 mL). The solution was stirred at room temperaturefor 90 minutes when it was quenched by addition of 2 drops of water. Thesolution was dried in vacuo and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 28 mg of the product (81%) as a clear gel. The NMR dataof this compound shows two rotamers in a ratio of 70:30. ¹H NMR (300MHz, CDCl₃) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J=7Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H),3.40-3.52 (m, 2H), 3.46 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s,3H), 4.07 (pent, 4H, J=7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22-5.30(m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.9 ppm; MS (m/z) 584.1[M+H]⁺, 606.2 [M+Na]⁺.

(2-{Acetyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of[2-(acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) wasadded TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). Thesolution was stirred at room temperature for 1 hour. The reaction wasquenched by addition of methanol and aqueous 1N HCl. The product wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄ and concentrated in vacuo. The product was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 5.4 mg of the product (53%) as a white solid. The NMRdata of this compound shows two rotamers. ¹H NMR (300 MHz, CDCl₃) δ 1.67and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H),3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 27.5 and 28.8 ppm; MS (m/z) 428.2 [M+H]⁺, 450.2[M+Na]⁺.

Example 265 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Benzyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirredwith acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at roomtemperature over night. The reaction was quenched with a 10% aqueousNa₂CO₃ solution and the product was extracted with EtOAc. The organiclayer was dried and concentrated under reduced pressure. The product waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as aclear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H),1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H),2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H),4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m,1H), 7.18-7.33 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.9 ppm; MS (m/z)632.4 [M+H]⁺, 654.3 [M+Na]⁺.

(2-{Benzyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) wastreated with TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24mmol). The solution was stirred at ambient temperature for 1 hour, whenit was quenched with methanol. The solvent was removed under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 11 mg ofthe product (93%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.89 (s,3H), 2.03-2.15 (m, 2H), 2.14 (s, 3H), 3.30-3.47 (m, 2H), 3.50 (br s,2H), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (brs, 1H), 7.46 (br s, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.1 ppm; MS (m/z)476.3 [M+H]⁺, 498.3 [M+Na]⁺.

Example 266 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was addedformic anhydride (1 mL) and the solution was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated and the crude productcarried onto the next step. The NMR data of this compound shows tworotamers with the ratio of 70:30. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s,9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J=7 Hz), 1.74 (s, 3H),1.84-2.08 (m, 2H), 2.19 (s, 3H), 3.34-3.45 (m, 2H), 3.47 (d, 2H, J=7Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent,4H, J=7 Hz), 4.26-4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03and 8.19 (s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.1 ppm; MS(m/z) 570.1 [M+H]⁺, 592.2 [M+Na]⁺.

(2-{Formyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of crude[2-(formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was addedTMSBr (177 μL, 1.4 mmol) and 2,6-lutidine (163 μL, 1.4 mmol). Thesolution was stirred at room temperature for 1 hour when it was quenchedby addition of methanol and 1N aqueous HCl. The product was extractedwith EtOAc and purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 29 mg of the product asa white solid. The NMR data of this compound shows two rotamers with theratio of approximately 70:30. ¹H NMR (300 MHz, CD₃OD) δ 1.62 and 1.64(s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s,3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]⁺, 436.2 [M+Na]⁺.

Example 267 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(500 mg, 1.33 mmol), (2-aminomethyl)phosphonic acid diethyl esteroxalate (376 mg, 1.46 mmol), sodium triacetoxyborohydride (563 mg, 2.66mmol) in DMF (10 mL) was added acetic acid (380 μL, 6.65 mmol) at roomtemperature. The solution was stirred overnight when it was quenched byaddition of saturated aqueous sodium bicarbonate solution and EtOAc. Theorganic layer was separated and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to provide 500 mg(71%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.13-1.23 (m, 2H), 1.25 and 1.27 (t, 6H, J=7 Hz), 1.65-1.75 (m, 2H),1.77 (s, 3H), 2.13 (s, 3H), 2.80 (s, 1H), 3.14 (s, 2H), 3.41 (d, 2H, J=7Hz), 3.73 (s, 3H), 4.08 and 4.09 (pent, 4H, J=7 Hz), 4.20-4.30 (m, 2H),5.08 (s, 2H), 5.30 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 26.5ppm; MS (m/z) 528.1 [M+H]⁺, 550.2 [M+Na]⁺.

{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-methyl}-phosphonicacid

To a solution of({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was added TMSBr(49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). The solution wasstirred at room temperature for 1 hour when it was quenched by additionof methanol. The product was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.6 mg ofthe product as a white solid. ¹H NMR (300 MHz, CD₃OD and CDCl₃) δ 1.93(s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J=11 Hz), 3.42-3.53 (m, 2H), 3.60(s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; ³¹P (121.4MHz, CDCl₃) δ 8.5 ppm; MS (m/z) 372.2 [M+H]⁺, 743.2 [2M+H]⁺.

Example 268 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-({2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(188 mg, 0.5 mmol) was stirred with2-[(2-aminoethyl)phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid salt (315.8 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) for 2 hours atambient temperature. Sodium triacetoxyborohydride (159 mg, 0.75 mmol)was added to the solution and the reaction was allowed to proceed for 1hour. The reaction was quenched by addition of a saturated aqueoussolution of NaHCO₃ and the product was extracted with EtOAc. The organiclayer was removed under reduced pressure and the residue was resuspendedin a 10% TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentratedand the product was purified by RP HPLC using a C18 column with agradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 198 mg ofthe product as a white solid. The NMR data of this compound shows twodiastereomers at phosphorus in a ratio of approximately 45:55. ¹H NMR(300 MHz, CD₃OD) δ 1.23 and 1.24 (t, 3H, J=7 Hz), 1.38 and 1.52 (d, 3H,J=7 Hz), 1.97 and 1.98 (s, 3H), 2.14 (s, 3H), 2.44-2.66 (m, 2H),3.31-3.48 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.66 (d, 2H, J=5 Hz), 3.80 (s,3H), 4.10-4.27 (m, 2H), 4.90-5.10 (m, 1H), 5.20 (s, 2H), 5.73-5.82 (m,1H), 7.15-7.27 (m, 3H), 7.35-7.45 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ22.6, 24.3 ppm; MS (m/z) 561.9 [M+H]⁺.

Example 269 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-[Hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(38 mg, 0.1 mmol) was stirred with2-[(2-aminoethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid (63 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) for 2 hours at ambienttemperature. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was addedto the solution and the reaction was allowed to proceed for 1 hour. Thereaction was quenched by addition of a saturated aqueous solution ofNaHCO₃ and the product was extracted with EtOAc. The organic layer wasremoved under reduced pressure and the residue was re-suspended in 10%TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentrated and theproduct was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product(154-2). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.15-1.24 (m, 2H), 1.26(t, 3H, J=7 Hz), 1.48 (d, 3H, J=7 Hz), 1.93 (s, 3H), 2.10-2.25 (m, 2H),2.18 (s, 3H), 3.10-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.48-3.61 (m,2H), 3.77 (s, 3H), 4.04-4.21 (m, 2H), 4.29-4.40 (m, 2H), 4.81-4.92 (m,1H), 5.13 (s, 2H), 5.64 (t, 1H, J=7 Hz), 8.70-9.11 (m, 3H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 21.9 ppm; MS (m/z) 586.3 [M+H]⁺, 1171.4 [2M+H]⁺.

2-(Hydroxy-{2-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoyloxy)-propionicacid

A solution of2-[hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH₂Cl₂ (1 mL) wasstirred at ambient temperature for 10 minutes. The reaction was workedup by removal of the solvent. The residue was dissolved in THF (0.5 mL)and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. Thesolution was stirred at room temperature for 20 minutes when it wasacidified with 1N aqueous HCl solution. The resulting solution waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 6.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (d, 3H, J=7 Hz), 1.91 (s, 3H),2.13 (s, 3H), 2.12-2.28 (m, 2H), 3.12-3.33 (m, 2H), 3.41 (d, 2H, J=6Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71-4.88 (m, 1H), 5.16 (s, 2H),5.58-5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.0 ppm; MS (m/z) 458.3 [M+H]⁺, 480.3[M+Na]⁺.

Example 270 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (241 mg, 1.38 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.13 mL, 1.15 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.23 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature for one hour before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by silica gel columnchromatography, affording 110 mg (90%) of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.24 (dd, J=7, 8 Hz, 2H), 1.36 (t, 6H),1.86 (s, 3H), 2.17 (s, 3H), 2.43-2.57 (m, 2H), 3.04-3.17 (m, 1H), 3.47(d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.44(t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.18 ppm; MS (m/z) 560[M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (5 mL) and stirred at room temperature for 2 hours. Thereaction mixture was dried under reduced pressure and the product waspurified by RP-HPLC to provide 16 mg (80%) of the desired product as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15(s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J=7.2 Hz, 2H),3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.09 ppm; MS (m/z) 436 [M−H]⁻, 438[M+H]⁺.

Example 271 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was addedTMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). Thereaction solution was allowed stir at room temperature for one hourbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg(60%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.86 (s, 3H),2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J=7.2 Hz,2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4MHz, CD₃OD) δ 15.28 ppm; MS (m/z) 380 [M−H]⁻, 382 [M+H]⁺.

Example 272 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodiumbis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and theresulting mixture was allowed to stir at room temperature for 2 hours.The reaction mixture was quenched with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated to dryness. The residue waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz,2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s, 3H), 2.17 (s, 3H), 2.23 (m,1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H),5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.26ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-1,3-dimethyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (51 μL, 0.4 mmol) and 2,6-lutidine (46 μL, 0.4 mmol).The reaction solution was allowed stir at room temperature overnightbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 4.5 mg(33%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.37 (d, 3H),1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m, 2H),3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ21.47 ppm; MS (m/z) 422 [M−H]⁻, 424 [M+H]⁺.

Example 273 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

A solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(1.5 g, 4.46 mmol) in toluene (14 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-butyraldehyde (1.68 g, 5.35 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-butyraldehyde (495 mg, 1.49 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 1.3 g (83%) of the desired product as oil. ¹H NMR (300 MHz,CDCl₃) δ 0.01 (s, 9H), 1.03 (t, 3H), 1.10-1.21 (m, 2H), 2.15 (s, 3H),2.15-2.44 (m, 2H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.31-4.36 (m, 2H),5.10 (s, 2H), 6.34-6.38 (m, 1H), 9.28 (s, 1H) ppm.

6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(1.3 g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0°C. A solution of CeCl₃ (8.25 mL, 0.4M, MeOH: H₂O, 9:1) was added,followed by LiBH₄ (1.66 mL, 3.30 mmol of a 2M solution in THF). The icebath was removed and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was stirred for an additional 40minutes, whereupon TLC indicated complete consumption of startingaldehyde. The reaction was worked up by addition of aqueous 1N HCl andthe product was extracted with EtOAc. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and brine. The organiclayer was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to provide 948 mg (73%) of theproduct as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.07(t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 (m, 2H), 3.77(s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.34 (t,J=7.2 Hz, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.66 g) was soaked indichloromethane (6 mL) for 1 hour6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(260 mg, 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. The mixture was filtered and the filtrate was concentrated.The residue was purified by silica gel chromatography to provide 233 mg(77%) of the product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.08 (t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.14 (s, 3H), 2.35-2.43(m, 2H), 3.44 (d, J=7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H), 5.53 (t, J=7.2 Hz, 1H) ppm.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(230 mg, 0.5 mmol) in trimethylphosphite (1.5 mL, 12.75 mmol) was heatedto 100° C. for 4 hours. The reaction was worked up by removal of excesstrimethylphosphite under reduced pressure. The residue was dissolved inacetonitrile (1 mL) and TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580μL, 5.0 mmol) were added at 0° C. The reaction solution was allowed towarm to room temperature and stirred for 4 hours. The reaction wascooled to 0° C. and quenched with addition of MeOH. The reaction mixturewas dried under reduced pressure and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 77 mg (58%) of the product. ¹H NMR (300 MHz, CD₃OD) δ1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J=22 Hz), 3.46(t, 2H, J=6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J=7 Hz) ppm.;³¹P (121.4 MHz, CD₃OD) δ 25.65 ppm.; MS (m/z) 355 [M−H]⁻, 357 [M+H]⁺.

Example 274 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (233 mg, 1.32 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.21 mL, 1.21 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(100 mg, 0.22 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature overnight before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by preparativereverse-phase HPLC, affording 51 mg (42%) of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.07 (t, 3H), 1.24 (dd, 2H, J=7, 8 Hz),1.36 (t, 6H), 2.12 (m, 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m,1H), 3.00-3.14 (m, 1H), 3.44 (d, J=7.2, 2H), 3.79 (s, 3H), 4.12-4.37 (m,6H), 5.13 (s, 2H), 5.38 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ18.26 ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-3-ethyl-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-pent-3-enyl]-phosphonicacid

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (2 mL) and stirred at room temperature for 10 minutes.The reaction mixture was dried under reduced pressure and purified byRP-HPLC to provide 9.5 mg (61%) of the desired product. This materialwas dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reactionsolution was allowed stir at room temperature overnight before quenchingwith MeOH. The reaction mixture was dried under reduced pressure and theresidue was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.1 mg (65%) of thedesired product as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.10 (t,3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m, 1H), 3.05-3.20 (m, 1H),3.48 (d, J=7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 14.18 ppm; MS (m/z) 394 [M−H]⁻, 396[M+H]⁺.

Example 275 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester

To a solution of bromomethylphosphonate diisopropyl ester (680 mg, 2.62mmol) and6-(3-hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (11.0M inTHF; 2.6 mL). The reaction was heated at 70° C. for 2 hours. Aftercooling to ambient temperature, more bromomethylphosphonate diisopropylester (680 mg, 2.62 mmol) and lithium t-butoxide (11.0M in THF; 2.6 mL)were added. The reaction mixture was heated at 70° C. for a furtherhour, cooled, poured into a solution of lithium chloride (5% aqueous)and extracted with ethyl acetate. The organic extract was dried and theproduct was purified by chromatography on silica gel, eluting withhexane-ethyl acetate to provide 347 mg (35%) of the product as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.09 (t, 3H,J=7.5 Hz), 1.20-1.26 (m, 2H), 1.31 (t, 12H, J=6 Hz), 2.18 (s, 3H), 2.29(q, 2H, J=7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J=8.7 Hz), 3.78 (s, 3H),3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t,1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.26 ppm; MS (m/z) 593.3[M+Na]⁺.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyloxymethyl]-phosphonicacid

To a solution of{2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) wasadded 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786mL, 6.1 mmol). The mixture was stirred at room temperature for 3 hours,quenched with methanol (5 mL), concentrated, and partitioned betweenethyl acetate and 1N HCl (aqueous). The organic layer was concentratedto give the free phosphonic acid as a colorless oil (205 mg, 70%). Thismaterial (20 mg) was dissolved in a solution of trifluoroacetic acid(0.3 mL) and dichloromethane (2.7 mL) and stirred for 30 minutes atambient temperature. After concentration, the residue was purified by RPHPLC using a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile,0.1% TFA to provide the product, after lyophilization, as a white solid(10 mg). ¹H NMR (300 MHz, CDCl₃) δ 1.007 (t, 3H, J=7.5 Hz), 2.13 (s,3H), 2.32 (q, 2H, J=7.5 Hz), 3.41 (d, 2H, J=6.3 Hz), 3.56 (d, 2H, J=9Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J=6.3 Hz)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.8 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1[M+H]⁺.

Example 276 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-Allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of 6-allyloxy-4-hydroxy-3-methyl-phthalic acid dimethylester (8.06 g, 28.8 mmol) [synthesized according to: J. W. Patterson,Tetrahedron, 1993, 49, 4789-4798] and pyridine (11.4 g, 144.0 mmol) indichloromethane (DCM) (20 mL) at 0° C. was added triflic anhydride(12.19 g, 43.2 mmol). The reaction was stirred at 0° C. for 2 hoursafter which additional triflic anhydride (3 mL) was added. Stirring at0° C. was continued for an additional hour. The reaction mixture waspoured into a mixture of DCM and HCl (1N). The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layerswere dried over sodium sulfate. Filtration and evaporation of solventsin vacuo yielded a crude product, which was purified by silica gelchromatography to provide 8.39 g of the product as an oil. ¹H NMR (300MHz, CDCl₃): δ=2.32 (s, 3H), 3.89 (s, 6H), 4.60 (m, 2H), 5.33 (d, J=9.3Hz, 1H), 5.41 (d, J=18.6 Hz, 1H), 5.95 (m, 1H), 6.95 (s, 1H) ppm; ¹⁹FNMR (282 MHz, CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (8.39 g, 20.3 mmol) in toluene (20 mL) was addedtetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) anddiethylamine (2.97 g, 40.86 mmol) at room temperature under anatmosphere of nitrogen. Stirring at room temperature was continued untilall starting material was consumed. The crude reaction mixture waspartitioned between diethyl ether and HCl (0.1 N). The organic layer waswashed with brine and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded a crude material, which waspurified by silica gel chromatography to provide 4.16 g (55%) of thedesired product as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ=2.20(s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹F NMR (282 MHz,CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester

To a solution of6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (2.17 g, 5.85 mmol) in N-methylpyrrolidinone (15 mL) was addedlithium chloride (743 mg, 17.5 mmol) and triphenylarsine (179 mg, 0.585mmol). Tributylvinyltin (2.04 g, 6.43 mmol) was added followed bytris(tribenzylideneacetone)dipalladium(0)-chloroform adduct (90 mg,0.087 mmol). The reaction was placed under an atmosphere of nitrogen andheated at 60° C. for 18 hours. The reaction was cooled to roomtemperature and poured onto a mixture of ice (20 g), EtOAc (40 mL), andpotassium fluoride (1 g). Stirring was continued for 1 hour. The aqueouslayer was extracted with EtOAc and the organic extracts filtered throughCelite. The combined organic layers were washed with water and driedover sodium sulfate. Filtration and evaporation of solvents in vacuoyielded a crude material, which was purified by silica gelchromatography to provide 1.27 g (87%) of the product as an off-whitesolid. ¹H NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s,3H), 5.46 (dd, J=11.1, 1.2 Hz, 1H), 5.72 (dd, J=17.1, 0.9 Hz, 1H), 6.86(dd, J=17.1, 11.1 Hz, 1H), 7.14 (s, 1H), 10.79 (s, 1H) ppm.

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL).Tristriphenylphosphine rhodium chloride (150 mg) was added and thereaction was placed under an atmosphere of hydrogen. Stirring at roomtemperature was continued. After 14 hours, the solvents were removed invacuo and the crude material was purified by silica gel chromatographyto provide 1.14 g (88%) of the desired product as an off-white solid. ¹HNMR (300 MHz, CDCl₃): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q,J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.

1 6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). Thesuspension was heated at 60° C. After 14 hours, the reaction was cooledto room temperature and filtered. The solvents were removed in vacuo andthe crude material was purified by silica gel chromatography to provide0.976 g (83%) of the desired product as a colorless oil. ¹H NMR (300MHz, CDCl₃): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz,2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz,1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester

6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester (1.25 g, 4.28mmol) was heated at 210° C. under an atmosphere of nitrogen. After 14hours, the reaction was cooled to room temperature. The crude materialwas purified by silica gel chromatography to provide 0.971 g (77%) ofthe desired product as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ=1.14(t, J=7.8 Hz, 3H), 2.17 (s, 3H), 2.68 (q, J=7.8 Hz, 2H), 3.49 (m, 2H),3.86 (s, 3H), 3.89 (s, 3H), 4.89-5.01 (m, 2H), 5.93 (m, 1H), 11.22 (s,1H) ppm.

5 6-Allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester (0.971g, 3.32 mmol) was dissolved in MeOH (8 mL) at room temperature. Asolution of sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) wasadded and the suspension was heated at 55° C. After 16 hours, thereaction was cooled to room temperature and washed with diethyl ether.The aqueous layer was acidified (1N HCl) and the suspension wasextracted with EtOAc. The combined organic layers were dried over sodiumsulfate. Filtration and evaporation of solvents in vacuo yielded thedesired bis acid as a white solid (0.846 g, 98%, M⁺=263). The bis acidwas dissolved in acetic acid (6 mL) and HCl (conc., 1.5 mL). Thereaction was heated at 80° C. Zn dust (0.635 g, 9.72 mmol, each) wasadded in portions every hour for 7 hours. Stirring at 80° C. wascontinued for additional 10 hours. The reaction was cooled to roomtemperature, and water was added. The resultant suspension was extractedwith EtOAc. The combined organic extracts were washed with sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded the crude product, which waspurified by silica gel chromatography to provide 0.375 g (50%) of theproduct as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=1.14 (t, J=7.5 Hz,3H), 2.18 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.49 (m, 2H), 4.95 (d, J=17.1Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.23 (s, 2H), 5.98 (m, 1H), 7.66 (s,1H) ppm.

56-Allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857mmol), PPh₃ (337 mg, 1.286 mmol), and 2-trimethylsilylethanol in THF (3mL) at 0° C. was added diisopropyl azodicarboxylate (259 mg, 1.286mmol). The resulting yellow solution was allowed to warm to roomtemperature and stirred for one hour. The solvent was removed in vacuoand the crude material was dissolved in diethyl ether (3 mL). Hexanes(1.5 mL) were added. Triphenylphosphine oxide was removed by filtrationand the filtrate was concentrated and purified by silica gelchromatography to provide the desired product (261 mg, 92%) as a clearoil. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H),1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.54 (m, 2H), 4.28(m, 2H), 4.95 (d, J=17.1 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.15 (s, 2H),5.95 (m, 1H) ppm.

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydroisobenzofuran-5-yl]-acetaldehyde

A solution of6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(261 mg, 0.788 mmol) in MeOH (5 mL), CH₂Cl₂ (5 mL) and pyridine (50 μL)was cooled to −78° C. using a dry ice/acetone bath according to theprocedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. Astream of ozone was bubbled through the reaction via a gas dispersiontube until the reaction became blue in color (15 minutes). The ozoneline was replaced with a stream of nitrogen and bubbling continued foranother 15 minutes, by which time the blue color had disappeared. Tothis solution, at −78° C., was added thiourea (59.9 mg, 0.788 mmol) inone portion, and the cooling bath was removed. The reaction was allowedto warm to room temperature and stirred for 15 hours. The reactionmixture was filtered and then partitioned between CH₂Cl₂ and water. Theaqueous layer was extracted with CH₂Cl₂ one more time and the organicextracts were combined, washed with aqueous 1N HCl, saturated NaHCO₃ andbrine and dried over sodium sulfate. Filtration and evaporation ofsolvents in vacuo yielded the crude product, which was purified bysilica gel chromatography to afford 181 mg (69%) of the product as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz,3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H),4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-propionaldehyde(72.9 mg, 0.23 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-propionaldehyde(33 mg, 0.11 mmol) was added and the reaction mixture was heated foradditional 9 hours. The toluene was removed in vacuo, and the residuewas purified by silica gel chromatography to provide 77.6 mg (77%) ofthe desired product as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=0.03 (s, 9H), 1.15 (t, J=7.5 Hz, 3H), 1.21 (m, 2H), 1.93 (s, 3H), 2.21(s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.82 (d, J=6.9 Hz, 2H), 4.34 (m, 2H),5.18 (s, 2H), 6.38 (m, 1H), 9.35 (s, 1H) ppm.

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl₃(51.1 mg, 0.207 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The MeOH was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and dried over sodium sulfate. Filtrationand evaporation of solvents yielded a crude oil, which was purified bysilica gel chromatography to provide 57.2 mg (73%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz,3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H), 2.72 (q, J=7.8 Hz, 2H),3.52 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32(m, 1H) ppm.

6-(4-Bromo-3-methyl-but-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 152.1 mg) was added and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (151.3 mg,0.456 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 58.0 mg (87%) of the desired product. ¹H NMR (300 MHz, CDCl₃):δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20(s, 3H), 2.70 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.94 (s, 2H),4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m, 1H) ppm.

{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid

A solution of4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-enylbromide (58 mg, 0.132 mmol) in trimethylphosphite (0.8 mL) was heated at110° C. After 2 hours the reaction was complete. The reaction was cooledto room temperature and the excess trimethylphosphite was removed invacuo. The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and thereaction was stirred at room temperature. After 15 minutes, lutidine(155.7 mg, 1.453 mmol) was added and stirring at room temperature wascontinued. After 2 hours, additional trimethylsilyl bromide (202.2 mg,1.321 mmol) was added and stirring at room temperature was continued.After 4 hours, the reaction was quenched with MeOH (2 mL). The solventswere evaporated in vacuo, and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 2.3 mg (5.1%) of the free phosphonic acid. ¹H NMR(300 MHz, DMSO-d6): δ=1.07 (t, J=7.5 Hz, 3H), 1.84 (s, 3H), 2.14 (s,3H), 2.64 (q, J=7.5 Hz, 2H), 3.34 (m, 4H), 5.06 (m, 1H), 5.25 (s, 2H)ppm; ³¹P NMR (121 MHz, DMSO-d6): δ=22.19 ppm; MS=341 [M⁺+1].

Example 277 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

[2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-butyraldehyde(98.4 mg, 0.296 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-butyraldehyde(98.4 mg, 0.296 mmol) was added and the reaction mixture was heated foradditional 33 hours. After concentration, the residue was purified bysilica gel chromatography to provide 50.3 mg (48%) of the desiredproduct as a pale yellow oil.

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl₃(31.9 mg, 0.129 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The methanol was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and were dried over sodium sulfate.Filtration and evaporation of solvents in vacuo yielded a crude oil,which was purified by silica gel chromatography to provide 35.4 mg (70%)of the desired product. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H),1.10-1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J=7.5 Hz, 2H),2.72 (q, J=7.5 Hz, 2H), 3.54 (d, J=6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m,2H), 5.14 (s, 2H), 5.27 (m, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 90.7 mg) was added, and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (90.2 mg,0.272 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 32.0 mg (78%) of the desired product. The material was used inthe next step without further characterization.

[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C.After 2 hours, the reaction was complete. The reaction was cooled toroom temperature and the excess trimethylphosphite was removed in vacuo.The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and thereaction was stirred at room temperature. After 2 hours, a second batchof trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3hours, the reaction was quenched with MeOH (2 mL). The solvents wereevaporated in vacuo and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 15.7 mg (63%) of the product. ¹H NMR (300 MHz,DMSO-d6): δ=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q,J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; ³¹P NMR(121 MHz, DMSO-d6): δ=22.26 ppm; MS=355 [M⁺+1].

Example 278 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid(15.7 mg, 0.263 mmol) was added, followed by sodiumtriacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide27.7 mg (97%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30(t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q,J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H),5.15 (s, 2H), 5.51 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.39 ppm;MS=540 [M⁺+1].

{2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL)and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was addedand the reaction was stirred at room temperature. After 20 hours, thereaction was quenched with MeOH (0.3 mL). The solvents were evaporatedin vacuo and the crude material was purified by RP-HPLC (eluent:water/MeCN). The product-containing fractions were combined andlyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484M⁺+1].

The material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added andstirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified by RPHPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 7.6 mg (52%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d6): δ=1.07 (t, J=7.5 Hz, 3H), 1.84(s, 3H), 1.90 (m, 2H), 2.11 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 2.99 (m,2H), 3.43 (d, J=6.3 Hz, 2H), 3.51 (s, 2H), 5.26 (s, 2H), 5.45 (m, 1H)ppm; ³¹P NMR (121 MHz, DMSO-d6): δ=20.02 ppm; MS=384 [M⁺+1].

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid(20.5 mg, 0.342 mmol) was added, followed by sodiumtriacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide24.9 mg (65%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H),2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz,2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s,2H), 5.47 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.71 ppm; MS=554[M⁺+1].

{2-[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enylamino]-ethyl}-phosphonicacid

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL)and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was addedand the reaction was stirred at room temperature. After 20 hours, thereaction was quenched with MeOH (0.15 mL). The solvents were evaporatedin vacuo and the crude material was purified by RP-HPLC (eluent:water/MeCN). The product-containing fractions were combined andlyophilized to yield 8.0 mg of the free phosphonic acid [MS: 498 M⁺+1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added,and stirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified by RPHPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 4.4 mg (54%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d6): δ 1.05 (m, 6H), 1.60 (m, 2H),2.10 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 2.63 (q, J=6.9 Hz, 2H), 2.93 (m,2H), 3.45 (m, 4H), 5.24 (s, 2H), 5.36 (m, 1H) ppm.; ³¹P NMR (121 MHz,DMSO-d6): δ 16.93 ppm; MS=398 [M⁺+1].

Example 279 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-en-phosphonicacid (44.8 mg, 0.101 mmol), dicyclohexylcarbodiimide (52.6 mg, 0.254mmol), and phenol (95.8 mg, 1.018 mmol) were dissolved in pyridine-(0.3mL) and heated at 70° C. for 4 hours. The reaction mixture was cooled toroom temperature and the pyridine was removed in vacuo. The crudematerial was partitioned between DCM and HCl (0.1N). The aqueous layerwas extracted with DCM and the combined organic layers were dried oversodium sulfate. Filtration and evaporation of solvents in vacuo yieldeda crude material, which was used in the next step without furtherpurification.

The crude material was dissolved in MeCN (0.8 mL) and water (0.3 mL).Aqueous sodium hydroxide solution (2N, 0.8 mL) was added in portions(0.2 mL). After all starting material was consumed, the organic solventwas removed in vacuo and the crude material was partitioned betweenchloroform and aqueous HCl (1N). The aqueous layer was extracted withchloroform. The combined organic layers were dried over sodium sulfate.Filtration and evaporation of solvents yielded the crude product as amixture of mono phenyl ester and the symmetrical anhydride.

The crude material of the previous step and ethyl (L)-alaninehydrochloride salt (78.1 mg, 0.509 mmol) were dissolved in DMF (0.4 mL).DMAP (1.2 mg, catalytic) was added, followed by diisopropylethylamine(131.3 mg, 1.018 mmol). Stirring at room temperature was continued.After 20 minutes, complete conversion of the anhydride was observed.After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring at roomtemperature was continued. The reaction was filtered and the crudereaction solution was purified by RP-HPLC (eluent: water/MeCN). Theproduct-containing fractions were combined and lyophilized to yield theproduct (15.7 mg, 25% over three steps) as a white powder. ¹H NMR (300MHz, CDCl₃): δ=0.03 (s, 9H), 1.13-1.28 (m, 8H), 2.03 (s, 3H), 2.19 (s,3H), 2.62-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m,3H), 4.30 (m, 2H), 5.14 (s, 2H), 5.31 (m, 1H), 7.11-7.17 (m, 3H),7.25-7.30 (m, 2H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.04, 27.73 ppm;MS=615 [M⁺+1].

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester (7.5 mg, 0.012 mmol) was dissolved in TFA/DCM (10%, 0.3mL) at −20° C. The reaction mixture was warmed to 0° C. and stirred atthis temperature for 45 minutes. Pyridine (0.09 mL) was added thesolvents were removed in vacuo. The crude material was purified byRP-HPLC (eluent: water/MeCN). The product-containing fractions werecombined and lyophilized, yielding a white powder (5.5 mg, 87%). ¹H NMR(300 MHz, CDCl₃): δ=1.12-1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H),2.65-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m, 3H),5.22 (s, 2H), 5.36 (m, 1H), 7.11-7.16 (m, 3H), 7.24-7.30 (m, 2H), 7.72(m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.11, 27.57 ppm; MS=515[M⁺+1].

Example 280 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid

A mixture of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) in amixture of methanol (20 mL) and water (7 mL) was stirred at roomtemperature for one hour. The solution was acidified with 1N HCl. Theprecipitate was collected by suction filtration and washed with water togive the desired product (1.2 g, 83%). ¹H NMR (300 MHz, CDCl₃) δ 0.02(s, 9H), 1.15-1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m,2H), 2.35-2.41 (m, 2H), 3.37 (d, 2H, J=7 Hz), 3.71 (s, 3H), 4.22-4.28(m, 2H), 5.07 (s, 2H), 5.13-5.17 (m, 1H) ppm; MS (m/z) 419.3 [M−H]⁻,443.2 [M+Na]⁺.

({6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminomethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirring was continued at roomtemperature for 20 minutes. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 54.8 mg (81%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.15-1.22(m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41(d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m,4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.01 ppm; MS (m/z) 568 [M−H]⁻, 592[M+Na]⁺.

{[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]-methyl}-phosphonicacid

To a solution of({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonicacid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was addedTMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol).The reaction was allowed to proceed overnight when it was completed asjudged by LCMS. The reaction mixture was quenched with MeOH andconcentrated to dryness. The residue was purified by preparativereverse-phase HPLC to afford 2.6 mg (9%) of desired product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46(m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 10.27 ppm; MS (m/z) 412 [M−H]⁻, 414[M+H]⁺.

Example 281 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminoethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirred at room temperature wascontinued for one hour. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 37 mg (54%) of thedesired product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m, 2H),2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H),3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H),5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.91ppm; MS (m/z) 584 [M+H]⁺.

{2-[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]-ethyl}-phosphonicacid

To a solution of(2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) wasadded TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63mmol). The reaction was allowed to proceed overnight, when it wascompleted as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC to afford 5.8 mg (29%) of desired product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m,4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm;³¹P (121.4 MHz, CD₃OD) δ 26.03 ppm; MS (m/z) 426 [M−H]⁻, 428 [M+H]⁺.

Example 282 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester

To a solution of[{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid (260 mg, 0.59 mmol) in DMF (6 mL) and phenol (555 mg, 5.9 mmol) wasadded dicyclohexyl carbodiimide (1.21 g, 5.9 mmol) and DMAP (36 mg,0.295 mmol). The reaction mixture was heated to 140° C. for 30 minutes.After cooling to room temperature, the mixture was partitioned betweenEtOAc/Hexane (1:1) and 5% aqueous LiCl solution. The organic layer waswashed with 5% aqueous LiCl solution repeatedly, then dried over Na₂SO₄.After removal of solvent, the residue was purified by silica gelchromatography to provide 75 mg (21%) of the desired product. MS (m/z)617 [M+Na]⁺.

{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH(0.1 mL) solution. The mixture was allowed to stir at room temperaturefor 16 hours. EtOAc was added and the resulting mixture was washed with1H HCl. The organic layer was concentrated to dryness and the residuewas purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 24.8 mg (38%) of the desiredproduct. MS (m/z) 517 [M−H]⁻, 541 [M+Na]⁺.

2-({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol).The solution was stirred at room temperature for 16 hours andconcentrated. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg(83%) of the desired product. MS (m/z) 641 [M+Na]⁺.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of2-({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5mL) and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was dried under reduced pressure and the residue waspurified by RP-HPLC to provide 18 mg (90%) of the desired product as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.18-1.34 (m, 3H), 1.36-1.48 (dd,3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H), 3.45 (m, 2H), 3.79(s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t, J=7.2Hz, 1H), 7.05-7.18 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 24.59, 26.13ppm; MS (m/z) 517 [M−H]⁻, 519 [M+H]⁺.

Example 283 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid

To a solution of2-{[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH(232 μL), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was dried under reduced pressure and the residuewas purified by RP-HPLC to provide 6 mg (77%) of the desired product asa clear oil. ¹H NMR (300 MHz, CD₃OD) δ 1.41 (d, J=7 Hz, 3H), 1.97 (s,3H), 2.16 (s, 3H), 2.59 (d, J=22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H),4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz,CD₃OD) δ 27.02 ppm; MS (m/z) 413 [M−H]⁻, 415 [M+H]⁺.

Example 284 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (1 g, ˜1.9 mmol) was combined with pyBOP (2 g, 4mmol) and DMAP (120 mg, 0.96 mmol). A solution of L-alanine ethyl esterhydrochloride salt (2.9 g, 19 mmol) and diisopropylethylamine (6.7 mL,38 mmol) in pyridine (5 mL) was added to the monoacid mixture and thereaction was stirred at room temperature for 12 hours. The reactionmixture was then concentrated and purified twice by columnchromatography (1% MeOH/CH₂Cl₂ 3% MeOH/CH₂Cl₂). The resulting oil wasdissolved in a vigorously-stirred solution of 10% TFA/CH₂Cl₂ (30 mL) at−40° C. The reaction was gradually warmed to 0° C. After about 3 hours,the reaction was complete. Pyridine (4.5 mL) was added, and the reactionmixture was concentrated. The product was purified by preparative TLC(5% MeOH/CH₂Cl₂) and concentrated to give 210 mg (21%) of the desiredproduct as a light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.83-7.70 (m,1H), 7.30-7.20 (m, 2H), 7.18-7.03 (m, 3H), 5.60-5.35 (m, 1H), 5.21 (s,2H), 4.17-3.95 (m, 3H), 3.79 (s, 3H), 3.60-3.40 (m, 3H), 2.80-2.60 (m,2H), 2.17 (m, 3H), 2.01 (m, 3H), 1.30-1.10 (m, 6H) ppm; ³¹P NMR (121MHz, CDCl₃) δ 28.0, 27.5 ppm; MS (m/z) 516 [M−H]⁻.

Example 285 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of trimethylphosphonoacetate (63 μL, 0.39 mmol) in THF (1mL) was added NaN(TMS)₂ (0.39 mmol, 0.39 mL) at ambient temperature.After 30 minutes, a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(69 mg, 0.156 mmol) in THF (1 mL) was added. The reaction mixture wasstirred for 2 hours, when a precipitate was observed. The reactionmixture was worked up by addition of a saturated aqueous solution ofammonium chloride and extraction of the product with EtOAc. The organicextract was dried and the product was purified using silica gelchromatography with 0-100% EtOAc-Hexanes to provide 40 mg of the desiredproduct as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H),1.20-1.26 (m, 2H), 1.79 (s, 3H), 2.17 (s, 3H), 2.42-2.72 (m, 2H), 3.19(ddd, 1H, J=4, 12, 23 Hz), 3.39 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.75 (s,3H), 3.77-3.84 (m, 6H), 4.27-4.34 (m, 2H), 5.12 (s, 2H), 5.24 (t, 1H,J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.1 ppm; MS (m/z) 565.2 [M+Na]⁺.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-2-phosphono-hex-4-enoicacid methyl ester

To a solution of2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was addedtrimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16mL) was added to the reaction at ambient temperature. The reaction wasallowed to proceed for 16 hours before it was concentrated to dryness.The residue was resuspended in a solution of DMF: H₂O (8:2, 1 mL) andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a whitepowder. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49(m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4, 12, 23 Hz), 3.38(3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t, 1H,J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 19.5 ppm; MS (m/z) 415.2 [M+H]⁺,437.2 [M+Na]⁺.

Example 286 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added asolution of 1N NaN(TMS)₂ in THF (0.88 mL, 0.88 mmol). The solution wasstirred at room temperature for 30 minutes, whereupon a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture wasstirred overnight when a precipitate was observed. The reaction mixturewas worked up by addition of a saturated aqueous solution of ammoniumchloride and extraction of the product with EtOAc. The organic extractwas dried and the product was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg(48%) of the product as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05(s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m,2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H),3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm;MS (m/z) 701.2 [M+Na]⁺.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-hydroxyoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

[2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (70 mg) was dissolved in a solution of 10%trifluoroacetic acid in dichloromethane (5 mL). After 10 minutes, themixture was concentrated and the product was purified by RP HPLC using aC18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 45 mg (75%) of the product as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H),3.38 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.77 (s, 3H), 4.33-4.43 (m, 4H),5.21 (s, 2H), 5.33 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.8ppm; MS (m/z) 601.2 [M+Na]⁺.

Example 287 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[hydroxy-(2,2,2-trifluoro-ethoxy)-phosphoryl]-4-methyl-hex-4-enoicacid

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (0.5 mL) was added asolution of 1N NaOH (aqueous; 0.06 mL) and N-methylpyrrolidinone (0.2mL). After 6.5 hours, another aliquot of 1N NaOH (0.06 mL) was added andthe mixture was stirred overnight. After concentration, the residue wassuspended in DMF (<1 mL), neutralized with a few drops of TFA andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 5.6 mg (72%) of the product as awhite powder after lyophilization. ¹H NMR (300 MHz, CD₃OD) δ 1.83 (s,3H), 2.16 (s, 3H), 2.43-2.51 (m, 1H), 2.59-2.70 (m, 1H), 3.13 (ddd, 1H),3.40 (d, 2H), 3.76 (s, 3H), 4.36-4.47 (m, 2H), 5.25 (s, 2H), 5.34 (t,1H, J=7 Hz) ppm; MS (m/z) 505.2 [M+Na]⁺.

Example 288 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

To a solution of6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) wasadded 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol)according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12,3889. After 10 minutes, another portion of2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA(35 μL, 0.20 mmol) were added. The reaction was allowed to proceed atroom temperature for an additional hour, after which it was quenched bythe addition of H₂O. The solution was stirred for another 10 minutes andconcentrated in vacuo to a small volume. The product was triturated withdiethyl ether and coevaporated from acetonitrile (4×10 mL) to providethe product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H),1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39(m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹P (121.4MHz, CDCl₃) δ 7.22; MS (m/z) 441 [M−H]⁻.

Example 289 Preparation of Representative Compounds of the Invention

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphoric acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

A solution of phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester(27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at roomtemperature for 3 hours. To the reaction solution was added2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowedto stir for an additional 2 hours at room temperature. The reactionmixture was diluted by addition of H₂O and the solution was stirred for2 more hours when it was concentrated. The residue was dissolved in asolution of 10% TFA/CH₂Cl₂ and stirred at room temperature for 9 hours.The reaction mixture was dried under reduced pressure and the productwas purified by reverse-phase HPLC to provide the desired product as awhite solid. ¹H NMR (300 MHz, CD₃OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47(d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H),5.50-5.61 (m, 1H); ³¹P (121.4 MHz, CD₃OD) δ 0.50; MS (m/z) 357 [M−H]⁻.

Example 290 Specific Embodiments of the Invention

Several compounds of the invention are presented below.

Example 291 Preparation of Representative Compounds of the Invention

Additional representative compounds of the invention, and intermediatesthereof, can be prepared according to the methods presented below.

Synthesis of phenacetaldehydes with variants at R₁, R₂

The parent compound (R₁=OMe; R₂=Me) is accessible by semi-synthesis frommycophenolic acid as follows:

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L) undernitrogen atmosphere was added sulfuric acid (10 mL) dropwise, and thesuspension was stirred at room temperature. After 2 hours, the reactionbecame homogeneous, and soon thereafter a precipitate was formed. Thereaction was allowed to stir at room temperature for 10 hours, at whichtime TLC indicated complete reaction. The reaction was cooled in an icebath to 10° C. and then filtered using a Buchner funnel. The filter cakewas washed with ice cold methanol (750 mL) followed by hexanes (750 mL)and then dried to give 497 g (95%) of the desired product as a solid: ¹HNMR (300 MHz, CDCl₃) δ, 1.81 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H),2.37-2.50 (m, 4H), 3.38 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H),5.13 (s, 2H), 5.22 (m, 1H), 7.17 (s, 1H).

To a solution (3.99 g, 11.9 mmol), PPh₃ (4.68 g, 17.9 mmol), anddiisopropyl azodicarboxylate (3.46 mL, 17.9 mmol) in THF (60 mL) at 0°C. was added a solution of 2-trimethylsilylethanol (2.05 mL, 14.3 mmol)in THF (20 mL). The resulting yellow solution was allowed to warm toroom temperature and stirred for 4 hours. The reaction was worked up byconcentrating the solution to dryness and addition of ether and hexanes.Triphenylphosphine oxide was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to provide 4.8 g(100%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ0.03 (s, 9H), 1.18-1.30(m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m,2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m,2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H).

A solution (9.6 g, 22 mmol) in MeOH (90 mL), CH₂Cl₂ (90 mL) and pyridine(0.7 mL) was cooled to −70° C. using a dry ice/acetone bath. A stream ofozone was bubbled through the reaction via a gas dispersion tube untilthe reaction became blue in color (1.5 hours). The ozone line wasreplaced with a stream of nitrogen and bubbling continued for another 30minutes, by which time the blue color had disappeared. To this solutionat −70° C. was added thiourea (1.2 g, 15.4 mmol) in one portion, and thecooling bath was removed. The reaction was allowed to warm to roomtemperature and stirred for 15 hours. The reaction was worked up byfiltration to remove solid thiourea S-dioxide, and then partitionedbetween CH₂Cl₂ and water. The organic layer was removed. The aqueouslayer was washed with CH₂Cl₂ and the organic extracts were combined,washed with aqueous 1N HCl, saturated NaHCO₃ and brine, and dried invacuo. The residue was purified by silica gel chromatography to afford7.3 g (99%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H),1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz),4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz).

R₁ Variants

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The aldehyde is dissolved in an organic solvent such as methanol andsodium borohydride is added. At the end of the reaction, aqueous HClsolution is added and the solvent is removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting alcohol is dissolved in an organic solvent such asdichloromethane (DCM). Pyridine and acetic anhydride are added andstirring at room temperature is continued. At the end of the reactionadditional DCM is added and the solution is washed with aqueous HClsolution, aqueous sodium bicarbonate solution, and dried over sodiumsulfate. Filtration and evaporation of the solvent in vacuo gives thecrude product. Further purification is achieved by chromatography.

The acetate is dissolved in DCM and bromine is added, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. At the end of thereaction, additional DCM is added and the solution is washed withaqueous sodium thiosulfate solution and brine. The organic layer isdried over sodium sulfate. Filtration and evaporation of solvents yieldsthe crude material. Further purification is achieved by chromatography.

The product of the previous step, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued forone hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of the previous step is dissolved in an organic solvent suchas DCM or THF.1,1,1-tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinreagent) is added and the solution is stirred at room temperature,according to a procedure from J. Org. Chem., 1984, 48, 4155-4156. At theend of the reaction diethyl ether is added, followed by aqueous sodiumhydroxide solution. The layers are separated and the organic layer iswashed with aqueous sodium hydroxide solution, water, and dried oversodium sulfate. Filtration and evaporation of solvents yields the crudeproduct. Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such astoluene. P(isobutyl NCH₂CH₂)₃N, palladium(II) acetate, sodium tert.butoxide, and benzylamine are added and the mixture was heated at 80°C., according to a procedure from J. Org. Chem., 2003, 68, 452-459. Atthe end of the reaction, the mixture is cooled to room temperature andthe solvents are removed in vacuo. The crude material is purified bychromatography. Any residual acetate is removed by brief treatment withmethanolic sodium methoxide.

The benzyl-protected aniline is dissolved in an organic solvent such asDMF. Palladium on carbon is added and the reaction mixture is placedunder an atmosphere of hydrogen. At the end of the reaction, the mixtureis filtered through Celite. The solvents are removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting primary aniline is dissolved in an organic solvent such asTHF, acetonitrile, or DMF and is treated with formaldehyde and sodiumtriacetoxyborohydride as described in J. Org. Chem., 1996, 61,3849-3862. The reaction is quenched with aqueous sodium bicarbonate andthe product is extracted with an organic solvent such as ethyl acetate.The crude material is treated with di-t-butyl dicarbonate in an organicsolvent such as dimethylformamide and aqueous sodium hydroxide. Theresulting carbamate is purified by chromatography.

The primary alcohol product is dissolved in an organic solvent such asDCM or THF. 1,1,1-tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin reagent) is added and the solution is stirred at roomtemperature, according to a procedure from J. Org. Chem., 1984, 48,4155-4156. At the end of the reaction diethyl ether is added, followedby aqueous sodium hydroxide solution. The layers are separated and theorganic layer is washed with aqueous sodium hydroxide solution, water,and dried over sodium sulfate. Filtration and evaporation of solventsyields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DCM orTHF and is treated with the mixed anhydride of formic and pivalic acids,according to a procedure from Recl. Trav. Chem. Pay-Bas, 1982, 101, 460.At the end of the reaction, the solvent and all volatiles are removed invacuo and the crude product is further purified by chromatography.

The product is dissolved in an organic solvent such as DCM or THF.1,1,1-Tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinreagent) is added and the solution was stirred at room temperature,according to a procedure from J. Org. Chem., 1984, 48, 4155-4156. At theend of the reaction diethyl ether is added, followed by aqueous sodiumhydroxide solution. The layers are separated and the organic layer iswashed with aqueous sodium hydroxide solution, water, and dried oversodium sulfate. Filtration and evaporation of solvents yields the crudeproduct. Further purification is achieved by chromatography.

R₂ Variants

The starting material is dissolved in an organic solvent such as DMF andreacted with N-chlorosuccinimide, according to a procedure from J. Med.Chem., 1996, 39, 4181-4196. After the starting material is consumed thereaction mixture is poured into water and the product is extracted withdiethyl ether. The combined organic layers are dried over sodiumsulfate. Filtration and evaporation of the solvent yields a crudereaction product.

The product of step one is dissolved in a mixture of organic solventssuch as methanol, DCM, and pyridine. The solution is cooled to −78° C.and ozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The starting material is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution, and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The product of step one is dissolved in an organic solvent such asbenzene. Trifluoromethanesulfonyl chloride anddichlorotris(triphenylphosphine)rhuthenium are added and the solution isdegassed. The reaction mixture is heated at 120° C., according to aprocedure from J. Chem. Soc., Perkin Trans. 1, 1994, 1339-1346. At theend of the reaction the mixture is cooled to room temperature and thesolvent is removed in vacuo. Further product purification is achieved bychromatography.

Synthesis of Olefins and Linkers to Phosphonates

The phenacetaldehyde (5.3 g, 15.8 mmol) in toluene (50 mL) was heated at100° C. with 2-(triphenyl-phosphanylidene)-propionaldehyde (6.8 g, 20.5mmol) overnight. After concentration, the residue was purified by silicagel chromatography to provide 4.24 g (72%) of the unsaturated aldehydeas a pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74(s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s,1H).

The trimethylsilyethyl protected aldehyde is treated withdiethylphosphite in a solvent such as acetonitrile in the presence of abase such as triethylamine to afford the hydroxy phosphonate, accordingto a procedure such as that reported in Tetrahedron, 1995, 51, 2099. Thehydroxy phosphonate is O-alkylated and then the protecting group isremoved by treatment with either trifluoroacetic acid ortetrabutylammonium fluoride to generate the desired methoxy phosphonateanalog.

Alternatively, the aldehyde is mixed with diethyl(2-aminoethyl)phosphonate and treated with a reducing agent such assodium triacetoxyborohydride to generate the amino phosphonate analog.

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

Polymer-supported triphenylphosphine is soaked in DCM for 1 hour. Theallylic alcohol and carbon tetrabromide are sequentially added. When thereaction is complete, the mixture is filtered and the filtrateconcentrated. The bromide is purified as necessary by chromatography.

The allylic bromide is treated in an inert organic solvent such asdimethylformamide with an alkali metal salt of ethyldiethoxyphosphorylacetate (prepared by reacting ethyldiethoxyphosphorylacetate with sodium hexamethyldisilazide or sodiumhydride) to afford the ethoxycarbonyl phosphonate, according to aprocedure such as that described in WO 9522538. The carboxylic estergroup is converted to both the carboxylic amide and the hydroxymethylgroups according to the methods conventionally utilized for amideformations and ester reductions. For example, the carboxylic ester issaponified with aqueous lithium hydroxide. The acid is activated withethyl chloroformate and reduced with sodium borohydride to generate,after removal of the protecting group, the hydroxymethyl phosphonateanalog. The acid is also converted to its acyl chloride and then reactedwith ethylamine to afford the amide analog.

The aryl acetaldehyde is coupled with 2-(diethoxyphosphoryl)-but-3-enoicacid ethyl ester to generate the 2-vinyl substituted ester, according toa procedure such as that reported in Synthesis, 1999, 282. The 2-vinylgroup is converted to the 2-cyclopropyl group under cyclopropanationconditions such as those described in Tetrahedron Lett. 1998, 39, 8621.The ester is converted to the alcohol, which, optionally, can be furthersubjected to reactions such as that described below to generate variousphosphonate-containing mycophenolic acid analogues.

The allylic alcohol is treated with bromomethylphosphonic aciddiisopropyl ester in the presence of a base such as lithium t-butoxidein a solvent such as dimethylformamide. The phenol protecting group isthen removed by treatment with trifluoroacetic acid.

The phenacetaldehyde can alternatively be converted to the allylphosphonium salt, according to a procedure such as that reported in J.Org. Chem. 1987, 52, 849. The phosphonium salt is then treated with thecommercially available 3,3,3-trifluoro-2-oxo-propionic acid ethyl esterand a base such as sodium hydride to generate the 2-trifluoromethylsubstituted ester. The ester is converted to the alcohol, which,optionally, can be further subjected to reactions described earlier togenerate mycophenolic acid analogues with various side chains containingthe phosphonate group.

Introduction of R₄ Variants

The enone (synthesis reviewed in Tetrahedron, 1985, 41, 4881-4889) andthe diene (Chem. Pharm. Bull., 1989, 37, 2948-2951) are dissolved-in anorganic solvent such as toluene, stirred at room temperature for 24hours and heated to reflux for additional 5 hours, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. The reaction mixtureis cooled to room temperature and the solvent removed in vacuo. Thecrude reaction product is further purified by chromatography.

The product of step one is dissolved in an organic solvent such as DCMand m-chloroperbenzoic acid is added, according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, thesolution is poured into aqueous sodium hydrogen sulfite solution. Theorganic layer is washed with saturated aqueous sodium bicarbonatesolution and is dried over sodium sulfate. Filtration and evaporation ofsolvents yields the crude product.

The crude product is dissolved in an organic solvent such as toluene andtreated with dichlorodicyanoquinone (DDQ), according to a procedure fromJ. Med. Chem., 1996, 39, 4181-4196. At the end of the reaction thesolvent is removed in vacuo and the crude material is further purifiedby chromatography.

The product is dissolved in an organic solvent such as DCM and treatedwith boron trichloride at reflux temperature, according to a modifiedprocedure from J. Med. Chem., 1996, 39, 46-55. At the end of thereaction the solution is washed with aqueous HCl solution. The solutionis dried over sodium sulfate. Removal of the solvent yields the crudereaction product. Further purification is achieved by chromatography.

The product of the previous step and triphenylphosphine are dissolved inan organic solvent such as tetrahydrofuran (THF).Diisopropylazodicarboxylate (DIAD) is added dropwise at 0° C. Stirringis continued. A solution of 2-trimethylsilyl ethanol in THF is added andstirring is continued. At the end of the reaction, the solvent isremoved in vacuo. The crude reaction solid is extracted with a mixtureof organic solvents such as hexanes and diethylether. The washings arecombined and the solvents removed in vacuo. The desired product isfurther purified and separated from the undesired regioisomer bychromatography.

The starting material is dissolved in an organic solvent such asdimethylformamide (DMF) and reacted with N-chlorosuccinimide, accordingto a procedure from J. Med. Chem., 1996, 39, 4181-4196. After thestarting material is consumed the reaction mixture is poured into waterand the product is extracted with diethyl ether. The combined organiclayers are dried over sodium sulfate. Filtration and evaporation of thesolvents yields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as benzeneand reacted with dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide(DCC), and orthophosphoric acid according to a procedure from J. Am.Chem. Soc., 1966, 88, 5855-5866. At the end of the reaction, thesuspension is filtered and the organic layer washed with aqueous sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents yields the crude material. Further purificationis achieved by chromatography.

The product of step one is dissolved in an organic solvent such as DCMor THF and treated with Raney nickel, according to procedures reviewedin Chem. Rev., 1962, 62, 347-404. When all starting material isconsumed, the reaction is filtered and the solvent removed in vacuo.Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such as DCM andbromine is added, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. At the end of the reaction, additional DCM is added and thesolution washed with aqueous sodium thiosulfate solution and brine. Theorganic layer is dried over sodium sulfate. Filtration and evaporationof solvents yields the crude material. Further purification is achievedby chromatography on silica gel.

The starting material, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued for1 hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of step two is dissolved in a mixture of organic solventssuch as benzene and ethyl acetate. Tris(triphenylphosphine)rhodium(1)chloride is added and the reaction is placed under an atmosphere ofhydrogen, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. The solvents are removed in vacuo and the crude reaction isfiltered through silica gel. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DMF.Potassium carbonate and allyl bromide are added and stirring at roomtemperature is continued, according to a procedure from J. Med. Chem.,1996, 39, 4181-4196. After all the starting material is consumed,aqueous HCl solution and diethyl ether are added and the organic layeris collected and the solvent is removed in vacuo.

The crude material is dissolved in N,N-diethylaniline and the reactionmixture is heated at an elevated temperature of ca. 180° C. At the endof the reaction, the mixture is cooled to room temperature and pouredinto a mixture of aqueous HCl (2N) and ethyl actetate. The organic layeris washed with aqueous HCl (2N) and dried over sodium sulfate.Filtration and removal of the solvents yields the crude product. Furtherpurification is achieved by chromatography.

The product of step 2 is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The aldehyde is dissolved in an organic solvent such as THF and isreacted with triphenylphosphonium sec.propyl bromide and potassiumtert.butoxide, according to procedures reviewed in Chem. Rev., 1989, 89,863-927. At the end of the reaction, the solvent is removed in vacuo andthe crude material purified by chromatography.

Introduction of Linkers to Phosphonates

The phenols shown herein may optionally be alkylated with the reagent ofchoice. Optionally, the phosphonate moiety will be part of such areagent. Alternatively, it will be introduced in a subsequent step by avariety of means, of which three are illustrated above. For example, analkyl halide may be heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press, 1988). Alternatively, an epoxidemay be reacted with the anion of a dialkyl phosphinate. In a furtherexample, the phosphonate reagent may be the electrophile, e.g., anacetylide anion may be condensed with phosphorus oxychloride and theintermediate dichlorophosphonate quenched with ethanol to generate thediethyl ester of the desired phosphonic acid.

Example 316 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows.

[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid

This product was prepared using methods similar to those describedherein, e.g., in Examples 251 and 276. MS (negative mode): 369.3 [M⁺−1].

Example 317 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows.

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

Using methods similar to those described herein, e.g., in Example 261,the desired product was prepared, starting from Example 316. MS(positive mode): 546.3 [M⁺+1] & 568.3 [M⁺+Na].

Example 318 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows:

2-({2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

This product was prepared using methods analogous to those describedherein, e.g., in Examples 268 and 316, using2-[(2-amino-ethyl)-phenoxy-phosphinoylamino]-propionic acid ethyl esterin the reductive amination step. MS (positive mode): 559.4 [M⁺+1] &581.3 [M⁺+Na].

Example 319 Preparation of an Additional Representative MycophenolateCompound of the Invention

A specific compound of the invention can be prepared as follows:

2-((1-Ethoxycarbonyl-ethylamino)-{2-[4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoylamino)-propionicacid ethyl ester

This product was prepared by methods analogous to those describedherein, e.g., in Example 318, using2-[(2-aminoethyl)-(1-ethoxycarbonyl-ethylamino)-phosphinoylamino]-propionicacid ethyl ester in the reductive amination step. MS (positive mode):582.4 [M⁺+1] & 604.3 [M⁺+Na].

Example 330 Synthesis of Exemplary Compounds of the Invention

A representative compound of the invention 330.4 can be prepared asillustrated above and as described below.

Compound 330.3 (250 mg, 0.65 mmol) was dissolved in 10 mL of absoluteethanol (15 mL) under an argon atmosphere. Following the addition ofNaOH (29 mg, 0.72 mmol), the reaction mixture was stirred overnight atroom temperature. TLC (CHCl₃/MeOH, 9:1) showed completion of reaction.The reaction mixture was concentrated to a solid and dissolved in ethylacetate (20 mL). The solution was washed with deionized water (2×10 mL)and dried over Na₂SO₄. Concentration gave a solid that was purified bysilica gel column chromatography (CHCl₃/MeOH, 4:1), affording purecompound 330.4 as a solid (188 mg, 75%). ESI-MS m/z 383 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆): δ 7.32 (1H, s, ArH), 6.96 (2H, s, ArH), 4.31 (2H, d,J=9.9 Hz, OCH₂), 4.18-4.08 (4H, m, 2×OCH₂), 2.08 (3H, s, CH₃), 2.00 (3H,s, CH₃), 1.26 (6H, t, J=7.0 Hz, CH₃). ³¹P NMR (121.7 MHz,DMSO-d₆/external H₃PO₄)

ppm 20.0-20.4 (m); HPLC: 93% pure (Sphereclone 5 μL, H₂O: MeCN, 20 minlinear from 10-90% MeCN, 1.0 mL/min).

The intermediate compound 330.3 was prepared as follows.

a. Synthesis of Compound 330.1. 2-Methyl-5-nitrophenol (2.00 g, 13.05mmol) was dissolved in dry DMF (10 mL) under argon atmosphere and cooledto 0° C. Diethylphosphonomethyl-O-triflate (4.70 gm, 15.66 mmol) andcesium carbonate (6.38 gm, 19.58 mmol) were added sequentially. Thereaction mixture was stirred at 0° C. for 4 hrs. TLC (cyclohexane/EtOAc,1:1) showed completion of reaction. Deionized water (15 mL) was addedand the mixture was extracted with EtOAC (2×50 mL). The organic layerwas washed with 1N HCl (20 mL) followed by water (2×20 mL), dried overNa₂SO₄ and concentrated to a semi-solid. Purification by silica gelcolumn chromatography (cyclohexane/EtOAc, 1:1) afforded pure compound330.1 as an oil (3.86 g, 97%). ESI-MS m/z 304 [M+H]⁺.b. Synthesis of Compound 330.2. Compound 330.1 (2.8 g, 9.24 mmol) wasdissolved in 15 mL of absolute ethanol (15 mL) and 6N HCl (2 mL) underan argon atmosphere. Following the addition of SnCl₂.2H₂O (5.26 g, 27.72mmol), the reaction mixture was stirred overnight at room temperature.TLC (CHCl₃/MeOH, 9:1) showed completion of reaction. The mixture wasconcentrated to a semi-solid and dissolved in ethyl acetate (30 mL). Theethyl acetate layer was washed with deionized water (10 mL) and satd.NaHCO₃ (10 mL) and dried over Na₂SO₄. Concentration gave a solid thatwas used without purification. ESI-MS m/z 274 [M+H]⁺.c. Synthesis of Compound 330.3. Crude compound K-105-48 (900 mg, 3.38mmol) was dissolved in 15 mL of dry THF (15 mL) under an argonatmosphere. Following the addition of 5-methylisoxazole-4-carboxylicacid (381 mg, 3.00 mmol) and diisopropyl carbodiimide (511 μL, 3.30mmol), the reaction mixture was stirred 6 h at room temperature. TLC(CHCl₃/MeOH, 9:1) showed completion of reaction. The reaction mixturewas filtered and the filtrate concentrated to give a solid, which wasdissolved in ethyl acetate (25 mL). The solution was washed withdeionized water (2×10 mL) and dried over Na₂SO₄. Concentration gave asolid that was purified by silica gel column chromatography (CHCl₃/MeOH,95:5) to afford pure compound 330.3 as light yellow solid (680 mg, 55%).ESI-MS m/z 383 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.11 (1H, s, ArH),7.06 (2H, s, ArH), 4.29-4.20 (4H, m, OCH₂), 4.14 (2H, d, J=10.4 Hz,OCH₂), 2.76 (3H, s, CH₃), 2.14 (3H, s, CH₃), 1.37 (6H, t, J=7.0 Hz,CH₃). ³¹P NMR (121.7 MHz, DMSO-d6/external H₃PO₄)

ppm 19.7-20.0 (m); HPLC: 98% pure (Sphereclone 5 μL, H₂O: MeCN, 20 minlinear from 10-90% MeCN, 1.0 mL/min).

Example 331 Synthesis of Representative Prednisone Compounds of theInvention

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of prednisone 331.1 with the appropriate phosphonate toprovide compounds of the invention 331.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the primary hydroxy proton in 331.1,diethyl phosphonate triflate is added to afford ether 331.4.

Example 332 Synthesis of Representative Prednisone Compounds of theInvention

Representative compounds of the invention 332.3 can be prepared asillustrated above. Protection of prednisone 332.1 at the less hinderedprimary site furnishes alcohol 332.5, which is alkylated at the exposedhydroxy group with the appropriate phosphonate to provide 332.6. Removalof the protecting group completes the construction of analog 332.3. Aspecific compound can be prepared as follows.

Prednisone 332.1 is mono-protected as its TBS ether 332.7. Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate 332.8 is treated with TBAF to give the desired phosphonate332.9.

Example 500 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) wasadded diethyl cyanophosphonate (34.8 μL, 230 μmol) anddiisopropylethylamine (Hunig's Base, DIEA, 30.4 μL, 177 μmol). Thesolution was stirred at ambient temperature for 4 hours whendiethyl(aminomethyl)phosphonate oxalate (45.4 mg, 177 μmol) was added.The solution was stirred for 4 additional hours, when completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The productcollected from this chromatography step was sufficiently pure to becarried on to the next reaction. A small amount of the product (20 mg)was repurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%)to provide 12.9 mg (76%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆)δ 1.19 (t, 6H, J=7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J=7.2Hz), 4.81 (s, 2H), 6.81 (d, 2H, J=9 Hz), 7.71 (d, 2H, J=9 Hz), 8.40 (brs, 1H), 8.61 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.4. MS (m/z) 475.2[M+H]⁺, 597.2 [M+Na]⁺.

Example 501 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (60 mg, 126 μmol)in dry DMF (0.90 mL) was added trimethylsilyl bromide(bromotrimethylsilane, TMSBr, 130.6 μL, 1.010 mmol) at ambienttemperature. The solution was then heated at 70° C. for 4.0 hours, afterwhich the reaction mixture was allowed to cool to room temperature. Thesolvent volume was reduced to ˜700 μL in vacuo and diluted with H₂O (100μL). This solution was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 26.8 mg (51%) of the desiredcompound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H),3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.79 (d, 2H, J=9 Hz),8.07 (br s, 1H), 8.56 (s, 1H); MS (m/z) 419.2 [M+H]⁺.

Example 502 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 4 hours,when diethyl(aminoethyl)phosphonate oxalate (43.8 mg, 161 μmol) wasadded. The solution was stirred for 3 additional hours, by which timecomplete consumption of the starting materials was observed. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct collected from this chromatography step was sufficiently pure tobe carried on to the next reaction. A small amount of the product (32mg) was re-purified by RP HPLC on Cl₈ column using H₂O/acetonitrile(2-95%) to provide 19 mg (70%) of the pure product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H),3.13-3.22 (m, 2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80(d, 2H, J=9 Hz), 7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H).³¹P (121.4 MHz, DMSO-d₆) δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺.

Example 503 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (61 mg, 125 mmol)in dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 μmol) at ambienttemperature. The solution was then heated at 70° C. for 5.5 hours, whenLCMS analysis demonstrated the reaction to be 90% complete. The reactionmixture was allowed to cool to room temperature and stirred for anadditional 12 hours. The reaction was worked up by removal of thesolvent in vacuo and dissolving the residue in DMF/H₂O (800 μL, 1:1) and1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (2-95%) to provide 29 mg (53%) of thedesired compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71(br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H),8.15 (br s, 1H), 8.56 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS (m/z)431.3 [M−H]⁻.

Example 504 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 3 hours,when diethyl(aminopropyl)phosphonate oxalate (34.9 mg, 122.6 μmol) wasadded. The solution was stirred for 2 additional hours, whereuponcomplete consumption of the starting materials was observed. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct (65.5 mg) collected from this chromatography step wassufficiently pure to be carried on to the next reaction. A small amount(32.8 mg) was re-purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H),3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s,2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 31.9; MS (m/z) 503.2 [M+H]⁺.

Example 505 Synthesis of Exemplary Compounds of the InventionPreparation of(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester post silica column chromatography (32.2 mg, 66.2μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) atambient temperature. The solution was then heated at 70° C. for 1.0hour, when LCMS analysis demonstrated the reaction to be complete. Thereaction mixture was allowed to cool to room temperature, and water (60μL) and methanol (60 μL) were added. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 11.2 mg (38%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40(m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20(br s, 1H), 8.69 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z)447.3 [M−H]⁻.

Example 506 Synthesis of Exemplary Compounds of the InventionPreparation of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomeric mixture at phosphorus]

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) wereadded diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL,474.9 μmol). The solution was stirred at ambient temperature for 3.5hours, when a solution of(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionic acid ethyl estermono acetic acid salt (57.1 mg, 158.3 μmol; mixture of diastereomers atphosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5additional hours, whereupon complete consumption of the startingmaterials was observed. The solvent was removed in vacuo and the crudematerial was purified by silica gel chromatography using MeOH—CH₂Cl₂(10-30%). A small amount of the product (24.8 mg) was repurified by RPHPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 15.8 mg(65%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.27 (m,3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19(s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H),6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66(d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 26.6, 27.4. MS (m/z) 609.2 [M+H]⁺.

Example 507 Synthesis of Exemplary Compounds of the InventionPreparation of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid [diastereomeric mixture at phosphorus]

To a solution of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionicacid ethyl ester (mixture of diastereomers at phosphorus; 40.0 mg, 65.7μmol) in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL) wasadded aqueous sodium hydroxide (1 N, 131.4 μL). The solution was stirredat ambient temperature for 4 hours. The solvents were removed in vacuoand the crude product was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (d, 2H, J=6.9 Hz), 1.79 (m, 2H), 3.21(s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J=8.7Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹P (121.4MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺.

Example 508 Synthesis of Exemplary Compounds of the InventionPreparation of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomerically pure at phosphorus]

To a solution of4-[(2,4-diaminopteridin-6-ylmethyl)-methyl-amino]benzoic acidhemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL) wereadded diethyl cyanophosphonate (53.0 μL, 349.5 μmol) and DIEA (138.0 μL,806.7 μmol). The solution was stirred at ambient temperature for 2.5hours, whereupon (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionicacid ethyl ester mono acetic acid salt (diastereomerically pure atphosphorus; 268.9 μmol) in DMF (500 μL) was added. The solution wasstirred for 30 additional minutes, whereupon complete consumption of thestarting materials was observed. The solvent was removed in vacuo andthe crude material was purified by silica gel chromatography usingMeOH—CH₂Cl₂ (10-30%). A small amount of the product (40.0 mg) wasrepurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 28.7 mg (75.1%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.15 (t, 3H, J=7.2 Hz), 1.44 (d, 3H, J=6.9 Hz), 2.26 (m, 2H), 3.23 (s,3H), 3.51 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H),6.81 (d, 2H, J=9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J=9.3Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6. MS(m/z) 609.2 [M+H]⁺.

Example 509 Synthesis of Exemplary Compounds of the InventionPreparation of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoylamino]propionicacid ethyl ester (mixture of diastereomers at phosphorus)

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL) wereadded diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL,209.4 μmol). The solution was stirred at ambient temperature for 3hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acidethyl ester mono acetic acid salt (mixture of diastereomers atphosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution wasstirred for 30 minutes when complete consumption of the startingmaterials was observed. An aliquot (66%) of the reaction was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%), yielding 27.2 mgof crude product. A small amount of the product (10 mg) was repurifiedby RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 4.2mg (26%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (t, 3H,J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51(m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80(d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d,2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆) δ29.5, 30.1. MS (m/z) 608.2 [M+H]⁺.

Example 510 Synthesis of Exemplary Compounds of the InventionPreparation of2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6-(diethoxy-phosphoryl)-hexanoicacid

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL) wereadded diethyl cyano phosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL,498.6 μmol). The solution was stirred at ambient temperature for 3.5hours when (L)-2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2μmol) was added. The solution was stirred for 48 additional hours. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct (87 mg) collected from this chromatography step was sufficientlypure to be carried on to the next reaction. An aliquot of the product(51.0 mg) was repurified by RP HPLC on C₁₈ column using H₂O/acetonitrile(2-95%) to provide 24.7 mg (44%) of the pure product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.18 (t, 6H, J=6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s,3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d,2H, J=9 Hz), 7.73 (d, 2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.56 (s, 1H);³¹P (121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3 [M]⁺.

Example 511 Synthesis of Exemplary Compounds of the InventionPreparation of2-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-6-(phosphoryl)hexanoicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino})-2′(L)-(6′-(phosphonic acid diethyl ester) hexanoic acid) post silicacolumn chromatography (20 mg, 34.6 μmol) in dry DMF (0.60 mL) was addedTMSBr (18.0 μL, 139.2 μmol) at ambient temperature. The solution wasthen heated at 70° C. for 18 hours, after which the reaction mixture wasallowed to cool to room temperature. The solvent was removed in vacuoand dissolved in DMF (400 μL) and water (60 μL). This solution waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 8.9 mg (49%) of the product as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77(s, 2H), 6.62 (br s, 1H), 6.80 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8.7Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS (m/z) 519.2 [M+H]⁺.

Example 512 Synthesis of Exemplary Compounds of the InventionPreparation of (L)-2-Cbz-Amino-hexanoic acid-6-phosphonic acid

To a suspension of (L)-2-amino-6-(diethoxyphosphonyl)hexanoic acid (106mg, 396.8 μmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μL, 2,381.0μmol) at ambient temperature. The solution was then heated at 70° C. for2 hours, after which the reaction mixture was allowed to cool to roomtemperature. The solvent was removed in vacuo. The crude material wasdissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzylchloroformate (79.3 μL, 555.5 μmol) was added and stirring at roomtemperature was continued. After 2 hours, the solution was washed withether (2 mL) and the aqueous layer was acidified with aqueous HCl topH 1. The aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried over sodium sulfate. Filtration andevaporation of solvents yielded a crude product, which was sufficientlypure for further transformations. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.65(m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z) 345.6 [M+H]⁺.

Example 513 Synthesis of Exemplary Compounds of the InventionPreparation of (L)-2-Amino-hexanoic acid 2′ TMS ethyl ester-6-phosphonicacid mono phenyl ester

To a solution of (L)-2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3mg, 397.9 μmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50μL). Stirring at room temperature was continued. After 22 hours completeconversion was observed. The solvents were removed in vacuo. The crudematerial was sufficiently pure for the next step.

One half of the crude material (198.9 μmol) was dissolved in toluene(3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol)was added and the reaction mixture was heated at 70° C. (oil bath).After 4 hours, the reaction was cooled to room temperature and thesolvent was removed in vacuo. The crude material was re-dissolved inmethylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) wasadded. Stirring at room temperature was continued. After 4 hrs thesolvents were removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) andaqueous sodium hydroxide solution (1N, 0.885 mL) was added. Stirring atroom temperature was continued. After 14 hours the solvent was removedin vacuo to provide the crude phosphonate mono phenyl ester (63.8 mg).This material was dissolved in 2-TMS ethanol (1.0 mL) and acetylchloride (20 μL) was added. Stirring at room temperature was continued.After 22 hours complete conversion to the carboxylate ester wasobserved. The solvents were removed in vacuo. The material wassufficiently pure for the next step.

One half of the crude material (75 μmol) was dissolved in ethanol (1.5mL). Pd/C (5%, 20 mg) was added and the reaction was placed under anatmosphere of hydrogen gas. After 1.5 hours Celite was added and thecrude reaction mixture was filtered through Celite. The solvents wereremoved in vacuo and the crude material was used in the next stepwithout further purification.

Example 514 Synthesis of Exemplary Compounds of the InventionPreparation of2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (22.7 mg, 60.0 mmol) in DMF (0.80 mL) wereadded diethyl cyano phosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL,180.0 μmol). The solution was stirred at ambient temperature for onehour when (L)-2-amino-6-monophenoxyphosphonatohexanoic acid 2′ TMS ethylester (70.5 μmol), suspended in DMF (0.2 mL), was added. The solutionwas stirred for 3.5 additional hours. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (5-95%) toprovide 19.4 mg (46%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ0.0 (s, 9H), 0.91 (t, 2H, J=8.1 Hz), 1.42-1.53 (m, 4H), 1.67-1.76 (m,4H), 3.24 (s, 3H), 4.10 (t, 2H, J=8.1 Hz), 4.29 (m, 1H), 4.86 (s, 2H),6.81 (d, 2H, J=9 Hz), 7.12 (m, 3H), 7.31 (m, 2H), 7.74 (d, 2H, J=9 Hz),8.14 (d, 1H, J=7.8 Hz), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.2;MS (m/z) 695.2 [M]⁺.

Example 515 Synthesis of Exemplary Compounds of the InventionPreparation of2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester

To a solution of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol)in DMF (0.70 mL) was added PyBOP (32.4 mg, 62.4 μmol), DIEA (21.4 mg,166.4 μmol) and (S) ethyl lactate (19.6 mg, 166.4 μmol). The reactionmixture was stirred at room temperature for one hour. The crude reactionmixture was purified by RP HPLC on C₁₈ column using H₂O/acetonitrile(5-95%) to provide 13.5 mg (81%) of the pure product as a mixture ofdiastereomers at phosphorus (4:1). ¹H NMR (300 MHz, CDCl₃) δ 0.0 (s,9H), 1.02 (t, 2H, J=8.7 Hz), 1.23 (t, 3H, J=9.3 Hz), 1.35 (d, 2.4H,J=6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H),4.03-4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57(d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30 (m, 2H), 7.63 (d,2H, J=7.5 Hz), 8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 30.5, 29.2; MS(m/z) 795.2 [M]⁺.

Example 516 Synthesis of Exemplary Compounds of the Invention

Compounds of the invention can generally be prepared as illustratedabove. For example, a specific compound of the invention can be preparedas follows.

Rofecoxib is treated in a solvent such as dimethylformamide ortetrahydrofuran with a base such as sodium hydride. When bubblingceases, E-1,4-dibromobutene is added in excess. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the mono-alkylated product isisolated by chromatography. The bromide so formed is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., Synthesis of carbon-phosphorusbonds, CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid.

Example 517 Synthesis of Exemplary Compounds of the Invention

Compounds of the invention can generally be prepared as illustratedabove (see also, Ind. J. Chem., Sect B, 1990, 10, 954.) A specificintermediate useful in the above process can be prepared as follows.

Ethyl 4-hydroxyphenylacetate is treated in a solvent such asdimethylformamide or tetrahydrofuran with a base such as sodium hydride.When bubbling ceases, E-1,4-dibromobutene is added in excess. Afterquenching the reaction with aqueous ammonium chloride and extracting theproduct with an organic solvent such as ethyl acetate, themono-alkylated product is isolated by chromatography. The bromide soformed is heated with triethylphosphite in a solvent such as toluene (orother Arbuzov reaction conditions: see Engel, R., Synthesis ofcarbon-phosphorus bonds, CRC press, 1988) to generate the diethyl esterof the desired phosphonic acid.

Example 518 Synthesis of Exemplary Compounds of the Invention

Appropriate oxidant(s) can convert the primary alcohol (5′-hydroxy)shown in 518-1.3 to a carboxylic acid or its corresponding ester. In thecase of an ester, an additional deprotection step will give thecarboxylic acid, 518-1.4. A variety of oxidation procedures exist in theliterature and can be utilized here. These include but are not limitedto the following methods: (i) pyridinium dichromate in Ac₂O, t-BuOH, anddichloromethane producing the t-butyl ester, followed by a deprotectionusing reagent such as trifluoroacetic acid to convert the ester to thecorresponding carboxylic acid (see Classon, et al, Acta Chem. Scand.Ser. B; 39; 1985; 501-504. Cristalli, et al; J. Med. Chem.; 31; 1988;1179-1183.); (ii) iodobenzene diacetate and2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) inacetonitrile, producing the carboxylic acid (See Epp, et al; J. Org.Chem. 64; 1999; 293-295. Jung et al; J. Org. Chem.; 66; 2001;2624-2635.); (iii) sodium periodate, ruthenium(III) chloride inchloroform producing the carboxylic acid (see Kim, et al, J. Med. Chem.37; 1994; 4020-4030. Homma, et al; J. Med. Chem.; 35; 1992; 2881-2890);(iv) chromium trioxide in acetic acid producing the carboxylic acid (seeOlsson et al; J. Med. Chem.; 29; 1986; 1683-1689. Gallo-Rodriguez et al;J. Med. Chem.; 37; 1994; 636-646); (v) potassium permanganate in aqueouspotassium hydroxide producing the carboxylic acid (see Ha, et al; J.Med. Chem.; 29; 1986; 1683-1689. Franchetti, et al; J. Med. Chem.; 41;1998; 1708-1715.) (vi) nucleoside oxidase from S. maltophilia to givethe carboxylic acid (see Mahmoudian, et al; Tetrahedron; 54; 1998;8171-8182.)

The preparation of 518-1.5 from 518-1.4 using lead(IV) tetraacetate (LGOAc) was described by Teng et al; J. Org. Chem.; 59; 1994; 278-280 andSchultz, et al; J. Org. Chem.; 48; 1983; 3408-3412. When lead(IV)tetraacetate is used together with lithium chloride (see Kochi, et al;J. Am. Chem. Soc.; 87; 1965; 2052), the corresponding chloride isobtained (1.5, LG=Cl). Lead(IV) tetraacetate in combination withN-chlorosuccinimide can produce the same product (1.5, LG=Cl) (see Wang,et al; Tet. Asym.; 1; 1990; 527 and Wilson et al; Tet. Asym.; 1; 1990;525). Alternatively, the acetate leaving group (LG) can also beconverted to other leaving group such as bromide by treatment oftrimethylsilyl bromide to give 518-1.5 ((see Spencer, et al; J. Org.Chem.; 64; 1999; 3987-3995).

The coupling of 518-1.5 (LG=OAc) with a variety of nucleophiles weredescribed by Teng et al; Synlett; 1996; 346-348 and U.S. Pat. No.6,087,482; Column 54 line 64 to Column 55 line 20. Specifically, thecoupling between 518-1.5 and diethyl hydroxymethylphosphonate in thepresence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) wasdescribed. It can be envisioned that other compounds with the generalstructure of HO-linker-POR^(P1)R^(P2) can also be used so long as thefunctional groups in these compounds are compatible with the couplingreaction conditions. There are many examples in the published literaturedescribing the coupling of 518-1.5 (LG=halogen) with a variety ofalcohols. The reactions can be facilitated with a number of reagents,such as silver(I) salts (see Kim et al; J. Org. Chem.; 56; 1991;2642-2647, Toikka et al; J. Chem. Soc. Perkins Trans. 1; 13; 1999;1877-1884), mercury(II) salts (see Veeneman et al; Recl. Trav. Chim.Pays-Bas, 106; 1987; 129-131), boron trifluoride diethyl etherate (seeKunz et al; Hel. Chim Acta; 68; 1985; 283-287), Tin(II) chloride (seeO'Leary et al; J. Org. Chem.; 59; 1994; 6629-6636), alkoxide (seeShortnacy-Fowler et al; Nucleosides Nucleotides; 20; 2001; 1583-1598),and iodine (see Kartha et al; J. Chem. Soc. Perkins Trans. 1; 2001;770-772). These methods can be selectively used in conjunction withdifferent methods in forming 518-1.5 with various leaving groups (LG) toproduce 518-1.6.

The introduction and removal of protecting groups from a compound is acommonly practiced art in organic synthesis. Many sources of informationof the art are available in the published literature, e.g. Greene andWuts, Protecting Groups in Organic Synthesis, 3^(rd) Ed., John Wiley &Sons, Inc., 1999. The main purpose is to temporarily transform afunctional group so that it will survive a set of subsequent reactionprocedures. Afterwards, the original functional group can be restored bya preconceived deprotection procedure. Therefore, the transformationsfrom 518-1.1 to 518-1.2, from 518-1.2 to 518-1.3, and from 518-1.6 to518-A are intended to allow the core components of the transformations(from 518-1.3 to 518-1.6) to occur while preserving the functionalgroups already exist in the compound structures.

The 5′-hydroxyl group of ribavirin (518-2) can be selectively protectedby an appropriate protecting group. The product, 518-3, can be treatedwith benzoyl chloride, an appropriate base, in the presence of catalyticamount of 4-dimethylaminopyridine, to convert 2′- and 3′-hydroxyl groupsto their corresponding benzoyl esters, 518-4. The 5′-hydroxyl group canbe selectively deprotected to give 518-5. Following procedure describedfor analogous compound in U.S. Pat. No. 6,087,482, FIG. 2, 518-4 can beconverted to 518-7 in a three-step sequence. Treating 518-7 with acoupling agent, such as trimethylsilyl trifluoromethanesulfonate, in thepresence of an appropriate alcohol containing a phosphonate group canproduce 518-8. Lastly, treating 518-8 with aqueous sodium hydroxide candeprotect the 2′- and 3′-hydroxyl groups to give 518-1. It is importantto point out that R_(P1) and R^(P2) in 518-8 and 518-1 do not need to bethe same.

A variety of compounds of the general structure 518-1.1 can either beprepared using procedures described in the literature, or be purchasedfrom commercial sources. The following are good sources for informationon the art of preparing a variety of compounds of the general structure518-1.1, Townsend, Chemistry of Nucleosides and Nucleotides, PlenumPress, 1994; and Vorbruggen and Ruh-Pohlenz, Handbook of NucleosideSynthesis, John Wiley & Sons, Inc., 2001. Some exemplary precursors,starting materials and their commercial sources include:

Compound 518-2.1 in Scheme 518-2 is prepared using method described (WO01/90121, page 115, table). The 5′-hydroxyl in 518-2.1 is protected ast-butyldimethylsilyl (TBDMS) ether. The 2′- and 3′-hydroxyl groups canbe protected as benzoyl (Bz) esters to give 518-2.2. The 5′-hydroxyl canthen be deprotected to give 518-2.3. Oxidation using iodobenzenediacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO)convert the primary alcohol to the corresponding acid 518-2.4. Furtheroxidation of 518-2.4 using lead tetraacetate can produce 518-2.5.Coupling between 518-2.5 and diethyl hydroxymethylphosphonate (availablefrom Sigma-Aldrich, Cat. No. 39, 262-6) effected by T-MS-OTf can afford518-2.6. Treating 518-2.6 with TMS—Br converts the phosphodiester to thecorresponding phosphonic acid 518-2.7. Deprotection of the 2′- and3′-hydroxyl gives 518-2.8 as an example of the generic structure 518-A,where Base is an adenine, R¹, R⁵, and R⁶ are hydrogen, R² is methylgroup, R³ and R⁴ are hydroxyl groups, linker is a methylene group, andR^(P1) and R^(P2) are both hydroxyl groups.

The phosphonic acids in 518-2.7 and 518-2.8 are used as examples forillustration purpose. Other forms of phosphonates can be access via thephosphonic acid, or other forms, such as the corresponding diesters. Seesection INTERCONVERSIONS OF PHOSPHONATES for details.

Many compounds of the generic structure 518-1.1 with the sugar moiety inits L-configuration are either commercially available or can be preparedby procedures described in the published literature. The oppositeD-configuration enantiomers of the L-nucleoside analogs previouslydiscussed can be prepared from the precursors that are the oppositeenantiomers of 518-3.1, 518-3.2, and 518-3.3. Scheme 518-3 describes thepreparation of the opposite enantiomers of 518-3.1, 518-3.2, and518-3.3.

The commercially available starting material 518-4.1 can be converted to518-4.4, which is the opposite enantiomer of 518-3.1, using the sequenceof reactions outlined above in Scheme 518-3. The osmium tetraoxidecatalyzed dihydroxylation reaction should introduce the diol selectivelyin the opposite face to the tert-butyldimethylsilyl (TBDMS) ether of thehydroxymethyl group. The diol in intermediate 518-4.3 can be protectedas TBDMS ether. Diisobutylaluminum hydride reduction of the lactone atlow temperature should produce 518-4.6, which can be converted to518-4.6 by acetylation. Deprotection of 518-4.6 should produce L-ribose(518-4.7). Acylation reaction can convert all hydroxyl groups in 518-4.7to the corresponding benzoyl esters. Standard coupling reactions with avariety of nucleobases should produce 518-4.10, which is the oppositeenantiomer of 518-3.3.

The synthesis of3-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazole (518-2)is described in US 2002/0156030 A1, page 6, paragraph 0078 to paragraph0079. Using this starting material, one can synthesize carboxamidecompound 518-1 (Scheme 518-4) or formamidine compound 518-1 (Scheme518-5) using the sequences of chemical transformations outlined inSchemes 518-4 and 518-5, respectively.

Appropriate protection, deprotection procedures (See Greene and Wuts,(1999) Protective Groups in Organic Synthesis) can be employed toprepare 518-3, in which the 5′-hydroxyl group is protected, while the2′, and 3′-hydroxyl groups are not (Schemes 518-4 and 518-5). Subsequentprotection, depretection procedures can introduce protecting groups suchas benzoyl group to the 2′- and 3′-hydroxyl, and leave the 5′-hydroxylgroup unprotected as in 518-4. Oxidation can convert the primary alcoholin 518-4 to the corresponding carboxylic acid or its ester. An optionaldeprotection of the ester can give the acid 518-5 as product. Furtheroxidation using oxidant such as lead tetraacetate can convert 518-5 to518-6, in which the leaving group is an acetate. Treating 518-6 with analcohol containing a phosphonate moiety in the presence of appropriatecoupling agent, such as trimethylsilyl trifluoromethanesulfonate, willgive 518-8 as product. Finally, treating 518-8 with the proceduredescribed in US 2002/0156030 A1, page 6, paragraph 0081, should give518-1 as product. It is important to point out that R^(P1) and R^(P2) in518-7, 518-8 and 518-1 do not need to be the same.

A solution of tert-butyl hydroperoxide (t-BuOOH) in benzene (68%, 3 eq)is added dropwise to a solution of allylic alcohol 518-1 (synthesized asdescribed in Tet. Letters (1997) 38:2355-58) and VO(acac)₂ in benzene(final concentration 0.1 M) at room temperature (Scheme 518-6). After 1h of stirring at room temperature, saturated aqueous Na₂S₂O₃ is added tothe reaction mixture. The resulting solution is extracted with EtOAc,washed with H₂O, and dried over sodium sulfate. After removal ofsolvent, the crude product 518-2 is purified by column chromatography onsilica.

Epoxide 518-2 and p-anisylchlorodiphenylmethane (1.5 eq) is dissolved inanhydrous pyridine (0.17 M) and stirred at 25° C. for 2d. Solvents wereremoved under reduced pressure and the residue dissolved in EtOAc. Theorganics were washed with water, saturated aqueous NaHCO₃, and driedover sodium sulfate. After removal of solvent, the crude product 518-3is purified by column chromatography on silica.

To a solution of methyltriphenylphosphonium bromide (2 eq) in anhydrousTHF at −78° C. is added n-butyllithium (2.2 eq). The solution is allowedto warm to room temperature and stirred for 20 min. After recooling to−78° C., this solution is added to fully protected epoxide 518-3 in THF(final concentration 0.06 M). The reaction mixture is allowed to warm toroom temperature and stirred for 12 h at which point H₂O is added andextracted with diethyl ether. The combined organics were dried oversodium sulfate. After removal of solvent, the crude product 518-4 ispurified by column chromatography on silica.

Sodium hydride (1 eq) and 2-amino-4-chloro-7H pyrrolo[2,3-d]pyrimidine(1 eq) were dissolved in anhydrous DMF (0.06 M) and stirred at 120° C.for 10 min. A solution of 518-4 in DMF is then added and the reactionmixture is stirred 12 h at 120° C. at which point the solvents wereevaporated under reduced pressure. The residue is dissolved in CH₂Cl₂,washed with H₂O, and dried over sodium sulfate. After removal ofsolvent, the crude product 518-5 is purified by column chromatography onsilica.

Compound 518-5 is dissolved in dichloromethane and added to a solutionof 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Aldrich, Dess-Martin periodinane, 4 eq) in dichloromethane (finalconcentration 0.06 M). The reaction mixture is stirred at roomtemperature for 4 d at which point it is diluted with EtOAc and pouredinto a solution of sodium thiosulfate in saturated aqueous sodiumbicarbonate solution. The organic layer is separated and dried oversodium sulfate. After removal of solvent, the crude product 518-6 ispurified by column chromatography on silica.

A solution of ketone 518-6 in anhydrous THF is added to a solution ofmethylmagnesium bromide (4 eq) in anhydrous THF (0.1 M) at −78° C. Thereaction mixture is stirred for 12 h at −60° C. at which point thereaction is quenched with saturated aqueous NH₄Cl solution. The mixtureis filtered over celite and washed with EtOAc. The combined organicswere washed with saturated aqueous NH₄Cl, water and dried over sodiumsulfate. After removal of solvent, the crude product is purified bycolumn chromatography on silica.

A solution of alcohol 518-7 in anhydrous THF (0.06 M) is treated with asolution of tetrabutylammonium fluoride (1.5 eq) in THF at roomtemperature. The reaction mixture is stirred for 3 h at which point thesolvents were evaporated. The crude desilylated diol 518-8 is purifiedby column chromatography on silica.

To a solution of diol 518-8 and benzenesulfonic aciddiisopropoxy-phosphorylmethyl ester (1.2 eq) in anhydrous DMF (0.1 M) isadded magnesium tert-butoxide (1 eq). The reaction mixture is heated to80° C. for 12 h. After cooling to room temperature, 1 N citric acid isadded and extracted with EtOAc. The organics were neutralized withsaturated aqueous NaHCO₃, washed with saturated aqueous NaCl, and driedover sodium sulfate. After removal of solvent, the crude product 518-9is purified by column chromatography on silica.

Compound 518-9 is dissolved in 80% acetic acid and stirred 12 h at roomtemperature. After removal of solvent, the crude product 518-10 ispurified by column chromatography on silica.

Phosphonate ester 518-10 and 2,6-lutidine (8 eq) is dissolved in CH₃CNand treated with trimethylsilyliodide (8 eq). After stirring for 3 h atroom temperature, triethylamine (8 eq) is added followed by methanol.After removal of solvent, the crude product 518-11 is purified by columnchromatography on silica.

Phosphonic diacid 518-11 is dissolved in 1,4-dioxane and treated with 4N NaOH and heated to 100° C. for 4 h. After cooling to room temperature,the reaction mixture is neutralized with 4N HCl. After removal ofsolvent, the crude product is purified by column chromatography onsilica to provide 518-12.

Compound 518-13 (Paquette et al J. Org. Chem. (1997) 62:1730-1736) istreated with p-methoxybenzyl bromide (1.5 eq.), sodium hydride (1.4 eq)in dry DMF at room temperature (Scheme 518-7). The reaction is monitorby TLC for the disappearance of 518-13. The reaction is quenched by theaddition of a saturated aqueous solution of ammonium chloride.Extraction by diethyl ether affords a crude product, which can bepurified by silica gel chromatography to give 518-14.

A solution of 518-14 in THF is added dropwise to a solution of n-BuLi(1.2 eq) in THF cooled at −78° C. under a nitrogen atmosphere. Thesolution is stirred for 1 h at −78° C. Excess of HMPA (1.4 eq) is added.After 10 min, a solution of MeI (5 eq) in THF is added. After another 5h at −78° C., 20% aqueous NaH₂PO₄ is added, and the mixture is warmed toroom temperature. Extraction with diethyl ether gives a crude product,which is purified by silica gel chromatography to give 518-15.

Dichlorodicyanoquinone (DDQ) is added to a mixture of compound 518-15 indichloromethane and water. After stirring at room temperature for 2 h.The mixture is extracted with dichloromethane to give a crude product,which is purified by silica gel chromatography to give 518-16.

To a solution of 518-16 in dioxane, is added triphenylphosphine (2 eq.),2-amino-6-chloropurine (2 eq) at room temperature. Diisopropylazodicarboxylate (2 eq, DIAD) is added dropwise via syringe. The mixtureis stirred at room temperature for another 3 h. Water is added to quenchthe reaction. Extraction with ethyl acetate gives a crude product, whichis purified by silica gel chromatography to give 518-17.

Alternatively, a nucleobase may be added by the methods described inCrimmins, M. T. (1998) Tetrahedron 54:9229-9272, such as palladiumcoupling to a cyclopentyl acetate.

To a solution of compound 518-17 in THF is added a 1 M solution oftetrabutylammonium fluoride (1.2 eq, TBAF) at room temperature. Afteranother few hours, a saturated solution of ammonium chloride is added.Extraction with ethyl acetate gives a crude product, which is purifiedby silica gel chromatography to give 518-18.

Compound 518-18, diethyl bromomethylphosphonate (1.5 eq), and lithiumt-butoxide (1.5 eq) are added to DMF sequentially. The mixture isstirred at 80° C. for several hours. After the mixture is cooled to roomtemperature, a 1 M solution of KH₂PO₄ is added. Extraction with ethylacetate gives a crude product, which is purified by silica gelchromatography to give 518-19.

To a solution of 518-19 in acetone, is added N-methylmorpholine N-oxide(2 eq) and osmium tetraoxide (0.2 eq). The mixture is stirred at roomtemperature for 16 h. A 1 M aqueous solution of sodium sulfite is added.After stirring at room temperature for another hour, the mixture isevaporated to remove most of acetone. The aqueous residue is frozen andlyophilized to give a crude product, which is purified by reversed phaseHPLC to give 518-20.

Iodotrimethylsilane (8 eq, TMS-I) is added to a mixture of 518-20,2,6-lutidine (8 eq) and acetonitrile. After stirring at room temperaturefor 2 h, the mixture is poured onto ice. The mixture is then frozen andlyophilized to give a residue, which is purified by reversed phase HPLCto give 518-21.

518-21 is dissolved in 4 N aqueous NaOH and refluxed for several hours.The mixture is cooled to room temperature, neutralized with 4 N HCl, andpurified with reversed phase HPLC to give 518-22.

Compound 518-22 can be converted to the correspondingdiphosphophosphonate 518-23, and prodrugs using known procedures.

3-Cyclopenten-1-ol 518-24(108 uL, 1.2 mmol, 1.2 eq) is dissolved in 5 mLof dry THF (Scheme 518-8). The solution is cooled to 0° C. A 1.35 Msolution of n-BuLi (0.89 mL, 1.2 mmol, 1.2 eq) is added via syringe.After 10 min, diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0mmol, 1.0 eq) is added. The mixture is stirred in a 45° C. bath for 3.5h. The reaction is quenched with a pH 7 aqueous phosphate buffer.Extraction with diethyl ether gave a crude product, which is purified bysilica gel chromatography (eluted with 45% ethyl acetate in hexane) togive 178 mg of 518-25 (68%).

To a solution of 518-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL of acetone,is added 273 mg of NaHCO₃ in 8 mL of water. The mixture is then cooledto 0° C. Oxone (519 mg, 0.85 mmol, 1.3 eq) in 4 mL of water is addedover 5 min in portions. The mixture is stirred vigorously for 2.5 h. Themixture is then evaporated in vacuo to remove most of the acetone. Theaqueous residue is extracted with ethyl acetate to give a crude product,which is purified by silica gel chromatography to give 518-26 as a clearoil.

To a solution of 518-26 (21 mg, 0.076 mmol, 1.0 eq) in 0.25 mL of DMF,is added cytosine (13 mg, 1.5 eq) and cesium carbonate (6 mg, 0.25 eq)and magnesium t-butoxide. The mixture is heated to 140° C. for severalhours. After cooling to room temperature, the reaction mixture ispurified by reversed phase HPLC to give 12.5 mg of 518-27 (42%). ¹H NMR(CDCl₃): δ 9.60 (br s, 1H), 8.96 (br s, 1H), 7.87 (d, 1H), 6.21 (d, 1H),4.84 (m, 1H), 4.78 (m, 2H), 4.43 (m, 1H), 4.08 (s, 1H), 3.72 (m, 2H),2.82 (m, 1H), 2.33 (m, 1H), 1.83 (m, 2H), 1.38 (m, 12H) ppm.

Alternatively, the methods in WO 03/105770 can be applied to add anucleobase with a nucleophilic amine to a cyclopentyl epoxide.

The conversion from 518-27 to 518-28 is described in Scheme 518-2 above.The conversion of 518-28 to the corresponding diphosphophosphonate518-29 and phosphorus prodrugs, e.g. 518-30 can be accomplished usingprocedures described herein.

Cyclopentyl intermediate 518-31 may be prepared by procedures analogousto those described in U.S. Pat. No. 5,206,244 and U.S. Pat. No.5,340,816 (Scheme 518-4). Diol 518-31 is converted to cyclopentenone518-32 and treated with IBr in the presence of the appropriatephosphonate alcohol to give 518-33. Iodide 518-33 is displaced withinversion to give cyclopentanone intermediate 518-34. Nystedmethylenation (U.S. Pat. No. 3,865,848; Aldrichim. Acta (1993) 26:14)provides exocyclic methylene 518-35, which may be deprotected to give518-36.

Cyclopentanone 518-34 may be a versatile intermediate to form othercompounds of the invention by reduction to cyclopentyl 518-37, or Wittigor Grubb olefination to alkenyl 518-38.

Scheme 518-10 shows intermediate 518-39 is converted to guanosylcyclopentenone 518-40 (J. Am. Chem. Soc. (1972) 94:3213), then treatedwith IBr and diethyl phosphomethanol to furnish iodide 518-41 (J. Org.Chem. (1991) 56:2642) Nucleophilic substitution with AgOAc affordsacetate 518-42. After methylenation using the procedure of Nysted (U.S.Pat. No. 3,865,848; Aldrichim. Acta 1993, 26, 14), to give 518-43, theacetate group is removed by the addition of sodium methoxide and theresulting alcohol is inverted by the Mitsunobo protocol, and a secondacetate deprotection produces 518-44. Desilylation withtetra-butylammonium fluoride (TBAF) of 518-44 will yield 518-45.

Example 519 Synthesis of Exemplary Compounds of the Invention

Synthesis of 519-1: To a solution of 3′-deoxyuridine (995 mg, 4.36 mmol)in 8 mL of anhydrous pyridine was added t-butyldiphenylsilyl chloride(TBDPS—Cl, 1.38 g, 5.01 mmol), and 4-dimethylaminopyridine (DMAP, 27 mg,0.22 mmol). The mixture was stirred at 23 C for 14 h and then cooled to0 C in a ice-water bath. To this mixture was added benzoyl chloride (735mg, 0.61 mL, 5.2 mmol). The mixture was warmed to 23° C. and stirred foranother 2 h. The mixture was concentrated in vacuo to give a paste,which was partitioned between water and ethyl acetate. The aqueous laterwas extracted once with ethyl acetate. The combined ethyl acetate layerwas washed sequentially with 1 M aqueous citric acid, saturated sodiumbicarbonate, and brine. It was dried over anhydrous sodium sulfate andconcentrated in vacuo to give a crude product as a yellow oil.Purification by silica gel chromatography (15-65% ethyl acetate inhexane) gave a colorless oil. Yield 1.35 g (54%). ¹H NMR (DMSO-d6): δ11.38 (s, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.77 (d, J=8.2 Hz, 1H) 7.70-7.40(m, 13H), 5.99 (s, 1H), 5.58 (m, 1H), 7.34 (d, J=8.2 Hz, 1H), 4.47 (m,1H), 4.03 (m, 1H), 3.84 (m, 1H), 2.43 (m, 1H), 2.21 (m, 1H), 1.03 (s,9H) ppm. MS (m/z) 571.1 (M+H⁺), 593.3 (M+Na⁺).

Example 520 Synthesis of Exemplary Compounds of the Invention

Synthesis of 520-2: To a solution of 519-1 (1.31 g, 2.3 mmol) in 5 mL ofanhydrous N,N-dimethylformamide was added benzyl chloromethyl ether(0.54 g, 3.45 mmol), N,N-diisopropylethylamine (446 mg, 0.60 mL, 3.45mmol). The mixture was stirred at 23° C. for 4 h. Water was added. Themixture was extracted with ethyl acetate. The organic layer was washedsequentially with 1 M aqueous citric acid, saturated sodium bicarbonate,and brine. It was dried over anhydrous sodium sulfate and concentratedin vacuo to give a crude product as a yellow oil, which was used in thenext step without further purification.

The crude product obtained above was dissolved in 9 mL of THF. Thesolution was cooled to 0 C. A 1 M solution of TBAF (4.6 mL, 4.6 mmol)was added via syringe. The mixture was warmed to 23° C. and stirred foranother 2 h. An additional 2.3 mL of 1 M TBAF was added. The mixture wasstirred for another 2 h at 23 C. Saturated aqueous ammonium chloride wasadded to the solution. The mixture was evaporated in vacuo to removemost of THF. The aqueous phase was extracted with ethyl acetate. Theaqueous layer was washed with brine. It was then dried over anhydroussodium sulfate and concentrated in vacuo to give a crude product as ayellow oil. Purification by silica gel chromatography (30-80% ethylacetate in hexane) gave a white solid. Yield of 520-2: 805 mg (77% fortwo steps). ¹H NMR (DMSO-d6): δ 8.04 (m, 3H), 7.67 (t, J=7.3 Hz, 1H),7.55 (t, J=7.6 Hz, 2H), 7.30 (m, 5H), 5.98 (s, 1H), 5.78 (d, J=7.9 Hz,1H), 5.55 (m, 1H), 5.31 (s, 2H), 5.22 (m, 1H), 4.57 (s, 2H), 4.41 (m,1H), 3.80 (m, 1H), 3.60 (m, 1H), 2.31 (m, 1H), 2.15 (m, 1H) ppm. MS(m/z) 453.1 (M+H⁺), 475.3 (M+Na⁺).

Example 521 Synthesis of Exemplary Compounds of the Invention

Synthesis of 521-3: To a solution of 520-2 (800 mg, 1.77 mmol) in 3.5 mLof a 1:1 mixture of acetonitrile/water was added iodobenzene diacetate(1.25 g, 3.89 mmol), and TEMPO (55 mg, 0.35 mmol). The mixture wasstirred at 23° C. for 14 h. The mixture was then froze in a −78° C. bathand lyophilized to give a solid residue. This residue was purified bysilica gel chromatography (0-15% methanol in dichloromethane). Product521-3 was obtained as a white solid. Yield: 735 mg (89%). ¹H NMR(DMSO-d6): δ 8.13 (d, J=7.6 Hz, 1H), 8.03 (d, J=7.7 Hz, 2H), 7.68 (m,1H), 7.58 (t, J=7.0 Hz, 2H), 7.29 (m, 5H), 6.04 (s, 1H), 5.85 (d, J=8.3Hz, 1H), 5.62 (m, 1H), 5.31 (s, 2H), 4.87 (m, 1H), 4.58 (s, 2H),2.40-2.20 (m, 2H) ppm. MS (m/z) 467.1 (M+H⁺), 489.3 (M+Na⁺).

Example 522 Synthesis of Exemplary Compounds of the Invention

Synthesis of 522-4: To a deoxygenated solution of 521-3 (730 mg, 1.57mmol) and pyridine (0.51 mL, 6.26 mmol) in 7 mL of anhydrous DMF, wasadded lead tetraacetate (3.47 g, 7.83 mmol). The mixture was stirred at23° C. for 14 h shielded from light. The mixture was diluted with 15 mLof ethyl acetate and 10 mL of water. This mixture filtered through a padof Celite and separated. The aqueous phase was extracted with another 10mL of ethyl acetate. The combined ethyl acetate extract was washed withbrine, dried over sodium sulfate, and evaporated in vacuo to give thecrude product as an oil. The crude product 522-4 was purified by silicagel chromatography (10-50% ethyl acetate in hexane). Products of twodiastereomers were obtained as a white foam. Yield: 400 mg (53%). ¹H NMR(DMSO-d6): δ 8.01 (m, 2H), 7.82-7.63 (m, 2H), 7.57 (m, 2H), 7.31 (m,5H), 6.58 (m, 1H), 6.17 (m, 1H), 5.83 (m, 1H), 5.65 (m, 1H), 5.31 (s,2H), 4.59 (s, 2H), 2.76 and 2.28 (m, 1H), 2.10 (m, 1H), 2.07 (s, 3H)ppm. MS (m/z) 481.0 (M+H⁺), 503.3 (M+Na⁺).

Example 523 Synthesis of Exemplary Compounds of the Invention

Synthesis of 523-5a: To a solution of 522-4 (300 mg, 0.63 mmol) in 6 mLof anhydrous dichloromethane was added diethyl hydroxymethylphosphonate(0.37 mL, 2.5 mmol), followed by trimethylsilyltrifluoromethanesulfonate (0.34 mL, 1.88 mmol). The mixture was stirredat 23° C. for 6 h. Triethylamine (0.44 mL, 3.15 mmol) was added,followed by water. The mixture was extracted with ethyl acetate. Theorganic layer was washed with 1 M aqueous citric acid, saturated sodiumbicarbonate, and brine. It was then dried over anhydrous sodium sulfate,and evaporated in vacuo to give a residue. This crude product waspurified by silica gel chromatography (75-95% ethyl acetate in hexane)to give two products, which were diastereomers of each other shown above(523-5a and 523-5b). Yield of 523-5a: 53 mg (14%). Yield of 523-5b: 129mg (35%).

Analytical data for 5a: ¹H NMR (Acetonitrile-d3): δ 8.04 (d, J=7.0 Hz,2H), 7.77 (d, J=7.9 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.53 (m, 2H), 7.33(m, 5H), 6.38 (d, J=4.0 Hz, 1H), 5.80 (d, J=8.2 Hz, 1H), 5.63 (m, 1H),5.52 (m, 1H), 5.41 (s, 2H), 4.64 (s, 2H), 4.17 (m, 4H), 4.08 (dd,J=13.8, 10.1 Hz, 1H), 3.92 (dd, J=13.7, 9.5 Hz, 1H), 2.66-2.42 (m, 2H),1.35 (t, J=7.0 Hz, 6H) ppm. MS (m/z) 589.2 (M+H⁺), 611.3 (M+Na⁺).Stereochemistry of 523-5a was confirmed by additional 2D NMRexperiments.

Analytical data for 523-5b: ¹H NMR (Acetonitrile-d3): δ 8.08 (d, J=7.3Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.55 (m, 2H), 7.43 (d, J=8.2 Hz, 1H),7.36 (m, 5H), 6.11 (d, J=2.4 Hz, 1H), 5.77 (d, J=8.3 Hz, 1H), 5.57 (m,2H), 5.41 (s, 2H), 4.66 (s, 2H), 4.12 (m, 5H), 3.88 (dd, J=14.0, 5.2 Hz,1H), 2.82 (m, 1H), 2.25 (m, 1H), 1.27 (t, J=7.0 Hz, 6H) ppm. MS (m/z)589.0 (M+H⁺), 611.2 (M+Na⁺).

Example 524 Synthesis of Exemplary Compounds of the Invention

Synthesis of 524-6: To a solution of 523-5a (110 mg, 0.19 mmol) in 3 mLof acetonitrile was added 2,6-lutidine (0.43 mL, 3.74 mmol), followed byiodotrimethylsilane (0.53 mL, 3.74 mmol). After stirring at 23 C for 30min, the mixture was heated to 40° C. and stirred at that temperaturefor another 4 h. The reaction mixture was cooled to 23° C. Triethylamine(0.52 mL, 3.74 mmol) was added, followed by water (10 mL). The aqueousmixture was extracted twice with 5 mL of diethyl ether. The resultingaqueous solution was frozen in a −78° C. bath and was lyophilized togive a yellow solid. This crude product was purified by reversed phaseHPLC to give 524-6 as a light yellow solid. Yield 26 mg (34%). MS (m/z)411.3 (M−H⁻).

Example 525 Synthesis of Exemplary Compounds of the Invention

Synthesis of 525-7: Phosphonate 524-6 (12 mg, 0.029 mmol),carbonyldiimidazole (47 mg, 0.29 mmol), and tri-n-butylamine (5.4 mg,0.029 mmol) were dissolved in 0.3 mL of anhydrous dimethylformamide(DMF). The mixture was stirred at 23° C. for 4 h. MeOH (0.020 mL) wasadded and the mixture was stirred for another 30 min. A solution oftributylammonium pyrophosphate (159 mg, 0.29 mmol) in 0.63 mL ofanhydrous DMF was added. The resulting mixture was stirred at 23° C. for14 h. The mixture was evaporated in vacuo to remove most of the DMF. Theresidue was dissolved in 5 mL of water and was purified by ion-exchangechromatography (DEAE-cellulose resin, 0-50% triethylammonium bicarbonatein water) to give a white solid, which was used directly in the nextreaction.

The product obtained above was dissolved in 2 mL of water. A 0.3 mL of a1 M solution of sodium hydroxide in water was added. The mixture wasstirred at 23° C. for 40 min. Acetic acid was added to adjust the pH ofthe solution to 5. The solution was diluted with water and purified withan ion-exchange column (DEAE-cellulose resin, 0-50% triethylammoniumbicarbonate in water) to give diphosphophosphonate 525-7 as a whitesolid, which is the triethylammonium salt of the structure shown above.Yield 10 mg (45% for two steps). ¹H NMR (D₂O): δ 7.79 (d, J=7.6 Hz, 1H),5.89 (m, 1H), 5.85 (d, J=7.6 Hz, 1H), 5.41 (m, 1H), 4.49 (m, 1H),4.02-3.65 (m, 2H), 3.06 (m, 18H), 2.20 (m, 2H), 1.14 (m, 27H) ppm. ³¹PNMR (D₂O): δ 7.46 (d, 1P), −9.45 (d, 1P), −23.11 (t, 1P) ppm. MS (m/z)467.0 (M−H⁻).

Example 526 Synthesis of Exemplary Compounds of the Invention

Synthesis of 526-8: To a solution of 524-6 (16 mg, 0.039 mmol) in 0.4 mLof water was added NaOH (7.8 mg, 0.19 mmol). The solution was stirred at23° C. for 1 h. Acetic acid (0.012 mL) was added to the solution. Themixture was then purified by reversed phase HPLC (eluted with 100%water) to give 4.6 mg of 526-8 as a white solid (38% yield). ¹H NMR(D₂O): δ 7.83 (d, J=8.3 Hz, 1H), 5.86 (d, J=3.4 Hz, 1H), 5.82 (d, J=7.9Hz, 1H), 4.48 (m, 1H), 3.68 (m, 1H), 3.37 (m, 1H), 2.16 (m, 2H) ppm. ³¹PNMR (D₂O): δ 12.60 (s, 1P) ppm. MS (m/z) 615.1 (2M−H⁻).

A solution of tert-butyl hydroperoxide (t-BuOOH) in benzene (68%, 3 eq)is added dropwise to a solution of allylic alcohol 526-1 (synthesized asdescribed in Tet. Lett., 38: 2355 (1997)) and VO(acac)₂ in benzene(final concentration 0.1 M) at room temperature (Scheme 526-1). After 1h of stirring at room temperature, saturated aqueous Na₂S₂O₃ is added tothe reaction mixture. The resulting solution is extracted with EtOAc,washed with H₂O, and dried over sodium sulfate. After removal ofsolvent, the crude product 526-2 is purified by column chromatography onsilica.

Epoxide 526-2 and p-anisylchlorodiphenylmethane (1.5 eq) is dissolved inanhydrous pyridine (0.17 M) and stirred at 25° C. for 2d. Solvents wereremoved under reduced pressure and the residue dissolved in EtOAc. Theorganics were washed with water, saturated aqueous NaHCO₃, and driedover sodium sulfate. After removal of solvent, the crude product 526-3is purified by column chromatography on silica.

To a solution of methyltriphenylphosphonium bromide (2 eq) in anhydrousTHF at −78° C. is added n-butyllithium (2.2 eq). The solution is allowedto warm to room temperature and stirred for 20 min. After recooling to−78° C., this solution is added to fully protected epoxide 526-3 in THF(final concentration 0.06 M). The reaction mixture is allowed to warm toroom temperature and stirred for 12 h at which point H₂O is added andextracted with diethyl ether. The combined organics were dried oversodium sulfate. After removal of solvent, the crude product 526-4 ispurified by column chromatography on silica.

Sodium hydride (1 eq) and 2-amino-4-chloro-7H pyrrolo[2,3-d]pyrimidine(1 eq) were dissolved in anhydrous DMF (0.06 M) and stirred at 120° C.for 10 min. A solution of 526-4 in DMF is then added and the reactionmixture is stirred 12 h at 120° C. at which point the solvents wereevaporated under reduced pressure. The residue is dissolved in CH₂Cl₂,washed with H₂O, and dried over sodium sulfate. After removal ofsolvent, the crude product 526-5 is purified by column chromatography onsilica.

Compound 526-5 is dissolved in dichloromethane and added to a solutionof 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Aldrich, Dess-Martin periodinane, 4 eq) in dichloromethane (finalconcentration 0.06 M). The reaction mixture is stirred at roomtemperature for 4 d at which point it is diluted with EtOAc and pouredinto a solution of sodium thiosulfate in saturated aqueous sodiumbicarbonate solution. The organic layer is separated and dried oversodium sulfate. After removal of solvent, the crude product 6 ispurified by column chromatography on silica.

A solution of ketone 526-6 in anhydrous THF is added to a solution ofmethylmagnesium bromide (4 eq) in anhydrous THF (0.1 M) at −78° C. Thereaction mixture is stirred for 12 h at −60° C. at which point thereaction is quenched with saturated aqueous NH₄Cl solution. The mixtureis filtered over celite and washed with EtOAc. The combined organicswere washed with saturated aqueous NH₄Cl, water and dried over sodiumsulfate. After removal of solvent, the crude product 526-7 is purifiedby column chromatography on silica.

A solution of alcohol 7 in anhydrous THF (0.06 M) is treated with asolution of tetrabutylammonium fluoride (1.5 eq) in THF at roomtemperature. The reaction mixture is stirred for 3 h at which point thesolvents were evaporated. The crude desilylated diol 526-8 is purifiedby column chromatography on silica.

To a solution of diol 526-8 and benzenesulfonic aciddiisopropoxy-phosphorylmethyl ester (1.2 eq) in anhydrous DMF (0.1 M) isadded magnesium tert-butoxide (1 eq). The reaction mixture is heated to80° C. for 12 h. After cooling to room temperature, 1 N citric acid isadded and extracted with EtOAc. The organics were neutralized withsaturated aqueous NaHCO₃, washed with saturated aqueous NaCl, and driedover sodium sulfate. After removal of solvent, the crude product 526-9is purified by column chromatography on silica.

Compound 526-9 is dissolved in 80% acetic acid and stirred 12 h at roomtemperature. After removal of solvent, the crude product 526-10 ispurified by column chromatography on silica.

Phosphonate ester 526-10 and 2,6-lutidine (8 eq) is dissolved in CH₃CNand treated with trimethylsilyliodide (8 eq). After stirring for 3 h atroom temperature, triethylamine (8 eq) is added followed by methanol.After removal of solvent, the crude product 526-11 is purified by columnchromatography on silica.

Phosphonic diacid 526-11 is dissolved in 1,4-dioxane and treated with 4N NaOH and heated to 100° C. for 4 h. After cooling to room temperature,the reaction mixture is neutralized with 4N HCl. After removal ofsolvent, the crude product is purified by column chromatography onsilica to provide 526-12.

Compound 526-13 (Paquette et al in J. Org. Chem. (1997) 62:1730-1736) istreated with p-methoxybenzyl bromide (1.5 eq.), sodium hydride (1.4 eq)in dry DMF at room temperature (Scheme 526-2). The reaction is monitorby TLC for the disappearance of 526-13. The reaction is quenched by theaddition of a saturated aqueous solution of ammonium chloride.Extraction by diethyl ether affords a crude product, which can bepurified by silica gel chromatography to give 526-14.

A solution of 526-14 in THF is added dropwise to a solution of n-BuLi(1.2 eq) in THF cooled at −78° C. under a nitrogen atmosphere. Thesolution is stirred for 1 h at −78° C. Excess of HMPA (1.4 eq) is added.After 10 min, a solution of MeI (5 eq) in THF is added. After another 5h at −78° C., 20% aqueous NaH₂PO₄ is added, and the mixture is warmed toroom temperature. Extraction with diethyl ether gives a crude product,which is purified by silica gel chromatography to give 526-15.

Dichlorodicyanoquinone (DDQ) is added to a mixture of compound 526-15 indichloromethane and water. After stirring at room temperature for 2 h.The mixture is extracted with dichloromethane to give a crude product,which is purified by silica gel chromatography to give 526-16.

To a solution of 526-16 in dioxane, is added triphenylphosphine (2 eq.),2-amino-6-chloropurine (2 eq) at room temperature. Diisopropylazodicarboxylate (2 eq, DIAD) is added dropwise via syringe. The mixtureis stirred at room temperature for another 3 h. Water is added to quenchthe reaction. Extraction with ethyl acetate gives a crude product, whichis purified by silica gel chromatography to give 526-17.

To a solution of compound 526-17 in THF is added a 1 M solution oftetrabutylammonium fluoride (1.2 eq, TBAF) at room temperature. Afteranother few hours, a saturated solution of ammonium chloride is added.Extraction with ethyl acetate gives a crude product, which is purifiedby silica gel chromatography to give 526-18.

Compound 526-18, diethyl bromomethylphosphonate (1.5 eq), and lithiumt-butoxide (1.5 eq) are added to DMF sequentially. The mixture isstirred at 80° C. for several hours. After the mixture is cooled to roomtemperature, a 1 M solution of KH₂PO₄ is added. Extraction with ethylacetate gives a crude product, which is purified by silica gelchromatography to give 526-19.

To a solution of 526-19 in acetone, is added N-methylmorpholine N-oxide(2 eq) and osmium tetraoxide (0.2 eq). The mixture is stirred at roomtemperature for 16 h. A 1 M aqueous solution of sodium sulfite is added.After stirring at room temperature for another hour, the mixture isevaporated to remove most of acetone. The aqueous residue is frozen andlyophilized to give a crude product, which is purified by reversed phaseHPLC to give 526-20.

Iodotrimethylsilane (8 eq, TMS-I) is added to a mixture of 526-20,2,6-lutidine (8 eq) and acetonitrile. After stirring at room temperaturefor 2 h, the mixture is poured onto ice. The mixture is then frozen andlyophilized to give a residue, which is purified by reversed phase HPLCto give 526-21.

526-21 is dissolved in 4 N aqueous NaOH and refluxed for several hours.The mixture is cooled to room temperature, neutralized with 4 N HCl, andpurified with reversed phase HPLC to give 526-22.

Compound 526-22 can be converted to the correspondingdiphosphophosphonate 526-23, and prodrugs using known procedures.

3-Cyclopenten-1-ol 526-24(108 uL, 1.2 mmol, 1.2 eq) is dissolved in 5 mLof dry THF The solution is cooled to 0° C. A 1.35 M solution of n-BuLi(0.89 mL, 1.2 mmol, 1.2 eq) is added via syringe. After 10 min,diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0 mmol, 1.0 eq)is added. The mixture is stirred in a 45° C. bath for 3.5 h. Thereaction is quenched with a pH 7 aqueous phosphate buffer. Extractionwith diethyl ether gave a crude product, which is purified by silica gelchromatography (eluted with 45% ethyl acetate in hexane) to give 178 mgof 526-25 (68%).

To a solution of 526-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL of acetone,is added 273 mg of NaHCO₃ in 8 mL of water. The mixture is then cooledto 0° C. Oxone (519 mg, 0.85 mmol, 1.3 eq) in 4 mL of water is addedover 5 min in portions. The mixture is stirred vigorously for 2.5 h. Themixture is then evaporated in vacuo to remove most of the acetone. Theaqueous residue is extracted with ethyl acetate to give a crude product,which is purified by silica gel chromatography to give 526-26 as a clearoil.

To a solution of 526-26 (21 mg, 0.076 mmol, 1.0 eq) in 0.25 mL of DMF,is added cytosine (13 mg, 1.5 eq) and cesium carbonate (6 mg, 0.25 eq)and magnesium t-butoxide. The mixture is heated to 140° C. for severalhours. After cooling to room temperature, the reaction mixture ispurified by reversed phase HPLC to give 12.5 mg of 526-27 (42%). ¹H NMR(CDCl₃): δ 9.60 (br s, 1H), 8.96 (br s, 1H), 7.87 (d, 1H), 6.21 (d, 1H),4.84 (m, 1H), 4.78 (m, 2H), 4.43 (m, 1H), 4.08 (s, 1H), 3.72 (m, 2H),2.82 (m, 1H), 2.33 (m, 1H), 1.83 (m, 2H), 1.38 (m, 12H) ppm.

The conversion from 526-27 to 526-28 is described in Scheme 526-2 above.The conversion of 526-28 to the corresponding diphosphophosphonate526-29 and phosphorus prodrugs, e.g. 526-30 can be accomplished usingprocedures described herein.

Cyclopentyl intermediate 526-31 may be prepared by procedures analogousto those described in U.S. Pat. No. 5,206,244 and U.S. Pat. No.5,340,816 (Scheme 526-4). Diol 526-31 is converted to cyclopentenone526-32 and treated with IBr in the presence of the appropriatephosphonate alcohol to give 526-33. Iodide 526-33 is displaced withinversion to give cyclopentanone intermediate 526-34. Nystedmethylenation (U.S. Pat. No. 3,865,848; Aldrichim. Acta (1993) 26:14)provides exocyclic methylene 526-35, which may be deprotected to give526-36.

Cyclopentanone 526-34 may be a versatile intermediate to form othercompounds of the invention by reduction to cyclopentyl 526-37, or Wittigor Grubb olefination to alkenyl 526-38.

Scheme 526-5 shows intermediate 526-39 is converted to guanosylcyclopentenone 526-40 (J. Am. Chem. Soc. (1972) 94:3213), then treatedwith IBr and diethyl phosphomethanol to furnish iodide 526-41 (J. Org.Chem. (1991) 56:2642) Nucleophilic substitution with AgOAc affordsacetate 526-42. After methylenation using the procedure of Nysted (U.S.Pat. No. 3,865,848; Aldrichim. Acta 1993, 26, 14), to give 526-43, theacetate group is removed by the addition of sodium methoxide and theresulting alcohol is inverted by the Mitsunobo protocol, and a secondacetate deprotection produces 526-44. Desilylation withtetra-butylammonium fluoride (TBAF) of 526-44 will yield 526-45.

Example 527 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 527-1: L-Xylose (36.2 g) and anhydrous CuSO₄ wereplaced in a 500 mL round bottomed flask. Acetone (220 mL) was added. Tothis slurry stirred at room temperature was added 3.6 mL of 96% sulfuricacid. The mixture was stirred for another 24 h at room temperature undera nitrogen atmosphere. The mixture is filtered to remove solid material.The solids were washed with 50 mL of acetone. To the combined filtratewas added 25.3 mL of conc. ammonium hydroxide. The precipitates wereremoved by filtration. The filtrate was evaporated in vacuo to give anoil, which was co-evaporated twice with absolute ethanol to give ayellow oil. The above crude product was stirred with 160 mL of 0.06 Maqueous HCl vigorously at room temperature for 2.5 h. The reactionmixture was homogeneous at the end of the reaction. Solid NaHCO₃ (3.26g) was added in portions. After gas evolution had stopped, the mixturewas filtered. The filtrate was frozen and lyophilized overnight to givea syrup, which was dissolved in ethyl acetate and dried over anhydrousNa2SO4 to give the desired diol as a yellow oil. Proton NMR showed theproduct to be >95% pure. Yield of this crude product: 44.5 g (96%). ¹HNMR (DMSO-d₆, 300 MHz): δ 5.79 (d, J=3.6 Hz, 1H), 5.13 (d, J=4.9 Hz,1H), 4.61 (t, J=5.6 Hz, 1H), 4.36 (d, J=3.6 Hz, 1H), 4.10-3.91 (m, 2H),3.60 (m, 1H), 3.51 (m, 1H), 1.37 (s, 3H), 1.22 (s, 3H) ppm

Example 528 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 528-2: 1,2-O-isopropylidene-L-xylose (5 g, 26.3mmol, 1.0 eq.) and 2-iodobenzoyl chloride (7.01 g, 26.3 mmol) weredissolved in anhydrous dichloromethane (25 mL). The solution was cooledin an ice-water bath. Triethylamine (3.85 mL, 27.6 mmol, 1.05 eq.) wasadded dropwise via syringe. The mixture was stirred at 0° C. for 30 minand slowly warmed to room temperature over 1 h. Water was added to thereaction mixture. The mixture was washed with 1 M aqueous HCl. Theaqueous wash was extracted with 20 mL of dichloromethane. The combinedorganic extract was washed with a mixture of 20 mL of brine and 5 mL ofsaturated aqueous sodium bicarbonate. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to give a brownoil. This crude product was purified by silica gel chromatography(eluted with 0-50% EtOAc in hexane) to give the desired mono-ester as ayellow oil. Yield: 7.6 g (69%). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.02 (d,J=7.3 Hz, 1H), 7.73 (dd, J=7.8, 1.7 Hz, 1H), 7.52 (t, J=7.3 Hz, 1H),7.29 (td, J=7.7, 1.8 Hz, 1H), 5.88 (d, J=3.7 Hz, 1H), 5.51 (m, 1H), 4.45(m, 2H), 4.12 (m, 1H), 1.38 (s, 3H), 1.24 (s, 3H) ppm. MS (m/z):calculated 420.01 (M+H⁺), 443.00 (M+Na⁺). found 420.9 (M+H⁺), 443.0(M+Na⁺).

Example 529 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 529-3: The product obtained in the previous step(7.6 g, 18.1 mmol, 1.0 eq.) was dissolved in 35 mL of anhydrousdichloromethane. Dess-Martin periodinane (9.6 g, 22.6 mmol, 1.25 eq.)was added. The mixture was stirred at room temperature for 14 h. A 1 Msolution of sodium sulfite (7.5 mL) was added. The resulting mixture wasstirred for another 2 h at room temperature. A saturated solution ofNaHCO₃ was added in portions to adjust the pH of the aqueous phase to 6.The two layers were separated. The aqueous phase was extracted twicewith 15 mL of dichloromethane. The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ for 4 h with good stirring. Itwas then filtered, and dried over excess amount of anhydrous MgSO₄overnight with good stirring. The mixture was filtered and concentratedin vacuo to give a clear oil as product, which was used without furtherpurification in the subsequent step. Yield: 6.7 g (89%). ¹H NMR(DMSO-d₆, 300 MHz): δ 8.02 (d, J=7.9 Hz, 1H), 7.71 (dd, J=7.8, 1.7 Hz,1H), 7.52 (t, J=7.4 Hz, 1H), 7.29 (td, J=7.6, 1.5 Hz, 1H), 6.16 (d,J=4.6 Hz, 1H), 4.85 (m, 1H), 4.63 (d, J=4.6 Hz, 1H), 4.54 (dd, J=12.2,2.7 Hz, 1H), 4.42 (dd, J=12.2, 4.3 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H)ppm. MS (m/z): calculated 458.99 (M+H₂O+Na⁺). found 459.03 (M+H₂O+Na⁺).

Example 530 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 530-4: The product obtained in the previous step(6.15 g, 14.7 mmol, 1.0 eq.) was dissolved in 29 mL of anhydrous THF.The solution was cooled in an ice-water bath. A 3.0 M solution of methylmagnesium bromide in diethyl ether (5.39 mL, 16.2 mmol, 1.1 eq.) wasadded dropwise via syringe. The mixture was stirred at 0° C. for 2 h.Aqueous citric acid solution (1 M, 10 mL) was added to the reactionmixture. The resulting mixture was evaporated in vacuo to remove most ofTHF. The aqueous residue was extracted twice with 10 mL of EtOAc. Theorganic extract was washed with saturated NaHCO₃ and brine. The organicphase was dried over anyhydrous sodium sulfate, filtered, and evaporatedin vacuo to give a white solid as product. Yield: 6.11 g (96%). ¹H NMR(DMSO-d₆, 300 MHz): δ 8.01 (dd, J=8.0, 1.0 Hz, 1H), 7.71 (dd, J=7.8, 1.7Hz, 1H), 7.52 (td, J=7.5, 1.0 Hz, 1H), 7.29 (td, J=7.7, 1.8 Hz, 1H),5.72 (d, J=3.7 Hz, 1H), 5.13 (s, 1H), 4.46 (dd, J=11.6, 2.3 Hz, 1H),4.20 (dd, J=11.7, 8.5 Hz, 1H), 4.12 (d, J=3.6 Hz, 1H), 4.08 (dd, J=8.5,2.1 Hz, 1H), 1.45 (s, 3H), 1.26 (s, 3H), 1.06 (s, 3H) ppm. MS (m/z):calculated 457.01 (M+Na⁺). found 457.27 (M+Na⁺).

Example 531 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 531-5: To a solution of 530-4 (6.1 g, 14.1 mmol)in 20 mL of anhydrous pyridine, was added triethylamine (3.13 mL, 22.5mmol), DMAP (0.343 g, 2.8 mmol), followed by benzoyl chloride (2.61 mL,22.5 mmol). The mixture was stirred at 70 C for 36 h, and then cooled toroom temperature. The mixture was evaporated in vacuo to remove most ofthe pyridine. The residue was acidified with 1 M aqueous citric acid.The resulting mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed with saturated NaHCO₃, and brine,dried over anhydrous Na₂SO₄, and evaporated in vacuo to give a crudeproduct. This crude product was purified by silica gel chromatography(0-35% ethyl acetate in hexane) to give 7.0 g (92%) of 5. ¹H NMR(DMSO-d₆, 300 MHz): δ 8.03 (d, J=8.2 Hz, 1H), 7.90 (d, J=7.5 Hz, 2H),7.79 (d, J=7.7 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.5 (m, 3H), 7.30 (t,J=7.6 Hz, 1H), 5.92 (d, J=3.7 Hz, 1H), 4.92 (d, J=3.5 Hz, 1H), 4.63 (m,1H), 4.46 (m, 2H), 1.50 (s, 3H), 1.39 (s, 3H), 1.25 (s, 3H) ppm. MS(m/z) 589.2 (M+H⁺), 611.3 (M+Na⁺). MS (m/z): calculated 561.04 (M+Na⁺).found 561.06 (M+Na⁺).

Example 532 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 532-6: To a solution of 531-5 (7.0 g, 13 mmol) in26 mL of glacial acetic acid, was added acetic anhydride (7.7 mL). Thesolution was cooled in an ice-water bath. Concentrated sulfuric acid(1.9 mL) was added dropwise via syringe over 10 min. The cooling bathwas removed and the solution was allowed to warm to room temperature andstirred at that temperature for another 20 h. The reaction mixture waspoured into a mixture of 75 mL of diethyl ether and 75 g of ice. Thelayers were separated and the aqueous layer was extracted with 75 mL ofdiethyl ether. The combined ether extract was stirred with 250 mL ofwater. Solid NaHCO3 was added in portions until gas evolution hadstopped. The layers were separated. The aqueous layer was extracted with75 mL of ether. The combined ether extract was washed with brine, driedover anhydrous MgSO₄, and concentrated in vacuo to give 6 as a yellowfoam. Two diastereomers of the same molecular weight were present in theproduct mixture, presumably the two anomers. Yield: 6.76 g (89%). Thiscrude product was used without further purification. MS (m/z):calculated 605.03 (M+Na⁺). found 604.93 (M+Na⁺).

Example 533 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 533-7: 532-6 (6.76 g, 11.6 mmol) was dissolved in22 mL of dichloromethane. The solution was cooled in an ice-water bath.A solution of SnCl₄ in dichloromethane (1.0 M, 29 mL, 29 mmol) was addedvia syringe. The cooling bath was removed and the mixture was warmed toroom temperature and stirred for another hour. The mixture was againcooled to 0° C. Triethylamine (15 mL) was added via syringe. Theresulting-solution was poured onto a mixture of 75 g of ice and 75 mL ofEtOAc. The mixture was filtered through a pad of Celite. The solids werewashed thoroughly with EtOAc. The combined filtrate was washed withsaturated NaHCO₃, brine, dried over Na₂SO₄, and concentrated in vacuo togive a crude product, which was purified by silica gel chromatography(25-75% EtOAc in hexane) to give 7 as a light yellow foam. Yield: 6.0 g(75%). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.00 (d, J=7.9 Hz, 1H), 7.86 (d,J=8.0 Hz, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.45 (m,3H), 7.25 (t, J=7.3 Hz, 1H), 5.28 (s, 1H), 5.07 (s, 1H), 4.65 (m, 2H),4.49 (m, 1H), 4.10-3.90 (m, 5H), 3.83 (dd, J=13.9, 9.0 Hz, 1H), 1.88 (s,3H), 1.69 (s, 3H), 1.18 (t, J=6.9 Hz, 6H) ppm. MS (m/z): calculated713.06 (M+Na⁺). found 713.08 (M+Na⁺).

Example 534 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 534-8: To a solution of 533-7 (4.7 g, 6.8 mmol) in30 mL of dichloromethane was added 27.2 mL of a 1.0 M aqueous solutionof KH₂PO₄. A 0.8 M solution of NaOCl in water was added. The mixture wasstirred at room temperature for 1 h. Methanol (10 mL) was added. SolidK2CO3 was added in portions until the pH of the aqueous phase reached9-10. The mixture was stirred for another hour at room temperature. An 1M aqueous solution of Na₂SO₃ (10 mL) was added and the mixture wasstirred for another 30 min at room temperature. The two layers wereseparated. The aqueous layer was further extracted with dichloromethane.The combined organic layer was washed with brine, dried over anhydrousNa2SO4, and evaporated in vacuo to give 534-8 as a yellow foam, whichwas used directly in the next step without further purification. ¹H NMR(DMSO-d₆, 300 MHz): δ 7.94 (d, J=7.8 Hz, 2H), 7.68 (t, J=7.5 Hz, 1H),7.54 (t, J=7.6 Hz, 2H), 5.28 (d, J=1.0 Hz, 1H), 5.05 (d, J=1.2 Hz, 1H),4.98 (t, J=5.6 Hz, 1H), 4.34 (dd, J=6.5, 4.6 Hz, 1H), 4.11-3.95 (m, 5H),3.86 (dd, J=13.7, 8.8 Hz, 1H), 3.76 (m, 1H); 3.63 (m, 1H), 1.93 (s, 3H),1.64 (s, 3H), 1.25 (t, J=7.0 Hz, 6H) ppm.

³¹P NMR (DMSO-d₆): δ 20.63 (s, 1P) ppm. MS (m/z): calculated 483.14(M+Na⁺). found 483.30 (M+Na⁺).

Example 535 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 535-9: To a mixture of 533-8 obtained above and6.8 mL of acetonitrile and 6.8 mL of water, was added iodobenzenediacetate (4.97 g, 15 mmol), and TEMPO (0.213 g, 1.36 mmol). The mixturewas stirred vigorously for 6 h at room temperature. It was then frozenand lyophilized to give a orange colored solid, which was dissolved indichloromethane and purified by silica gel chromatography (0-10% MeOH inCH2Cl2) to give 534-9 as a light yellow solid. Yield: 2.8 g (87% for twosteps). ¹H NMR (DMSO-d₆, 300 MHz): δ 13.39 (br s, 1H), 7.97 (d, J=7.8Hz, 2H), 7.70 (t, J=7.3 Hz, 1H), 7.56 (t, J=7.5 Hz, 2H), 5.35 (s, 1H),5.16 (s, 1H), 4.89 (s, 1H), 4.18 (dd, J=13.7, 8.8 Hz, 1H), 4.06 (m, 4H),3.88 (dd, J=13.4, 9.7 Hz, 1H), 1.86 (s, 3H), 1.69 (s, 3H), 1.24 (dt,J=7.0, 2.7 Hz, 6H) ppm. ³¹P NMR (DMSO-d₆): δ 20.79 (s, 1P) ppm. MS(m/z): calculated 473.12 (M−H⁻). found 472.95 (M−H⁻).

Example 536 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 536-10: To a solution of 535-9 (474 mg, 1.0 mmol)in 2.0 mL of anhydrous DMF, was added pyridine (238 mg, 3.0 mmol), andlead tetraacetate (1.33 g, 3.0 mmol). The mixture was stirred whileshielded from light for 7 h at room temperature. It was then poured intoa mixture of 10 g of ice and 10 mL of diethyl ether. The mixture wasfiltered to remove precipitates. The two layers of the filtrate wereseparated. The aqueous phase was extracted twice with ether. Thecombined ether extract was washed with 1 M citric acid, saturatedNaHCO₃, and brine. After drying with anhydrous MgSO4, the ether solutionwas concentrated in vacuo to give crude 536-10 as a colorless oil, whichwas used without further purification. Yield: 255 mg (52%). MS (m/z):calculated 511.13 (M+Na⁺). found 511.11 (M+Na⁺).

Example 537 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 537-11: To a solution of 536-10 (211 mg, 0.43mmol) in 2.0 mL of anhydrous acetonitrile, was addedO,O-bis(trimethylsilyl)uracil (443 mg, 1.73 mmol), and TMS-OTf (384 mg,1.73 mmol). The mixture was stirred at room temperature for 3 h. Anadditional 443 mg of O,O-bis(trimethylsilyl)uracil was added, and themixture was stirred for another 4 h at room temperature. 2,6-Lutidine(371 mg, 3.46 mmol) was added dropwise via syringe, followed by TMS-I(259 mg, 1.3 mmol). The mixture was stirred for another hour at roomtemperature and then poured onto 10 g of ice. The mixture frozen andfiltered through a pad of Celite. The filtrate was frozen andlyophilized to give a yellow solid, which was dissolved in water andpurified by reversed phase HPLC to give 537-11 as a white solid. Yield:20 mg (10%). MS (m/z): calculated 483.08 (M−H⁻). found 483.34 (M−H⁻).

Example 538 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 538-12: To a solution of 537-11 (17 mg, 0.035mmol) in 0.3 mL water, was added NaOH (4.3 mg, 0.11 mmol). Afterstirring at room temperature for 2 h, the mixture acidified withtrifluoroacetic acid and purified by HPLC to give 538-12 as a whitepowder. Yield: 5 mg (42%). ¹H NMR (D₂O, 300 MHz): δ 7.74 (d, J=8.2 Hz,1H), 5.97 (s, 1H), 5.78 (d, J=8.2 Hz, 1H), 5.10 (d, J=4.9 Hz, 1H), 3.86(dd, J=12.9, 10.0 Hz, 1H), 3.78 (d, J=4.7 Hz, 1H), 3.65 (dd, J=12.7, 9.3Hz, 1H), 1.10 (s, 3H) ppm. ³¹P NMR (D₂O): δ 14.60 (s, 1P) ppm. MS (m/z):calculated 337.04 (M−H⁻). found 337.38 (M−H⁻).

Example 539 Synthesis of Exemplary Compounds of the Invention Synthesisof 3′-Deoxy-CP

Example 540 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 540-2 To a stirred solution of 527-1 (50 mg, 0.11mmol) in 1 mL of acetonitrile under nitrogen was added2,4,6-triisopropylbenzenesulfonyl chloride (65 mg, 0.21 mmol), DMAP (26mg, 0.21 mmol), and triethylamine (22 mg, 0.21 mmol). The mixture wasstirred at room temperature for 4 h. Aqueous ammonia (29%, 1 mL) wasadded. The mixture was stirred at room temperature for 2 h. Extractionwith EtOAc, followed by purification by silica gel chromatography gave540-2 as a white solid. MS (m/z): calculated 468.15 (M+H⁺). found 468.0(M+H⁺).

Example 541 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 541-3: To a solution of 540-2 obtained above inacetonitrile was added 2,6-lutidine (118 mg, 1.10 mmol) and TMS-I (165mg, 0.84 mmol). The mixture was stirred at room temperature for 2 h.Triethylamine was added, followed by water. The mixture was then frozenand lyophilized to give a solid residue. This crude product was purifiedby reversed phase HPLC to give 541-3 as a white solid. Yield 44 mg (97%for two steps). MS (m/z): calculated 410.1 (M−H⁻). found 410.2 (M−H⁻).

Example 542 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 542-4: To solution of 541-3 (40 mg, 0-097 mmol) in0.5 mL of water was added NaOH (20 mg, 0.5 mmol). The solution wasstirred at room temperature for 30 min. Reversed phase HPLC purificationgave 542-4 as a white solid. Yield: 28 mg (94%). ¹H NMR (D₂O, 300 MHz) δ7.79 (d, J=7.6 Hz, 1H), 5.95 (d, J=7.6 Hz, 1H), 5.88 (d, J=2.8 Hz, 1H),5.40 (m, 1H), 4.42 (m, 1H), 3.78 (dd, J=12.8, 9.8 Hz, 1H), 3.55 (dd,J=13.1, 9.7 Hz, 1H), 2.20-2.05 (m, 2H) ppm. ³¹P NMR (D₂O, 300 MHz) δ14.66 ppm. MS (m/z): calculated 306.05 (M−H⁻). found 305.8 (M−H⁻).

Example 543 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 543-5: To phosphonic diacid 542-4 (9 mg, 0.029mmol) in 0.25 mL of DMF was added tributylamine (5.4 mg, 0.03 mmol)followed by carbonyldiimidazole (48 mg, 0.3 mmol). Reaction mixture wasstirred at room temperature for 4 h at which point MeOH (0.010 mL) wasadded and stirred for an additional 30 min. Tributyl ammoniumpyrophosphate (161 mg, 0.3 mmol) in DMF (0.64 mL) was added the reactionmixture stirred for 14 h. After the solvents were evaporated in vacuo,the crude product was purified by ion exchange HPLC (0-40% TEAB) to givethe triethylammonium salt of 543-5 as a white solid. Yield: 3 mg. ¹H NMR(D₂O, 300 MHz) δ 7.78 (d, J=7.6 Hz, 1H), 6.02 (d, J=7.6 Hz, 1H), 5.88(d, J=2.9 Hz, 1H), 5.42 (m, 1H), 4.41 (m, 1H), 4.05-3.62 (m, 2H), 3.05(q, J=7.4 Hz, triethylammonium), 2.23-1.95 (m, 2H), 1.13 (t, J=7.4 Hz,triethylammonium) ppm. ³¹P NMR (D₂O, 300 MHz) δ 7.58 (d), −8.34 (d),−22.71 (t) ppm. MS (m/z): calculated 465.98 (M−H⁻), found 466.16 (M−H⁻).

Example 544 Synthesis of Exemplary Compounds of the Invention Synthesisof 3′-Deoxy-CP

Example 545 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 545-2 To a stirred solution of1-O-methyl-2′-deoxy-D-ribose (23.9 g, 161.41 mmol) in pyridine undernitrogen was added t-butyldiphenylsilyl chloride (48 mL, 186 mmol)dropwise. When the addition was complete N,N-dimethyl-4-aminopyridinewas added as a solid. The reaction was stirred at room temperature for12 hr. and monitored by TLC. When the reaction was complete by TLC thepyridine was removed under vacuum. The oily residue was suspended inethyl acetate (150 mL) and a white solid formed. The mixture wasfiltered and the solid was washed with 50 mL additional ethyl acetate.The solid was then discarded. The organic filtrates were combined andwashed with water (2×100 mL), 1N HCl(aq) (2×100 mL) and sodiumbicarbonate(sat'd) (2×100 mL). The organic phase was collected and driedover MgSO₄(anh). Evaporation and purification by column chromatographyprovides the desired mixture of diastereomers 545-2: yield 31.15 g (500%). ¹H NMR (CD₃CN, 300 MHz): δ 1.08 m, 9H); 1.85 m 1H; 2.27 m 2H, 3.3 s3H, 3.7 m 2H, 3.90 m 1H; 4.27 m 1H; 5.06 m 1H, 7.45 m 6H, 7.76 m 4H.ppm.

Example 546 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 546-3: The alcohol 545-2 (5.00 g, 12.95 mmol) andtriphenylphosphine (6.79 g. 25.9 mmol) were dissolved in anhydrous THF(50 mL) under nitrogen at room temperature. To this stirring solutionwas added dropwise, a mixture of benzoic acid (3.162 g, 25.9 mmol) anddisopropylazodicarboxylate dissolved in anhydrous THF (30 mL). After theaddition was complete the reaction was stirred for 12 hr. at roomtemperature. After the reaction was complete by TLC, the solvent wasremoved under vacuum. The residue was suspended in diethyl ether (60mL). Hexane (120 mL) was added and the solid formed was filtered anddiscarded. The solvents were removed by rotary evaporation and theproducts 546-3 were purified by column chromatography (2% to 15% EtOAcin hexane): yield 3.074 g (48.4%). ¹H NMR (CD₃CN, 300 MHz): δ 0.98 m 9H,2.07 m 1H, 2.42 m 2H, 3.35 s 3H, 3.85 m 1H, 3.99 m 1H; 4.4 m 1H; 5.10 m1H, 5.69 m 1H; 7.30 m 1H; 7.47 m 5H, 7.65 m 6H, 7.80 m 1H; 7.95 m 1H;8.22 m 1H ppm.

Example 547 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 547-4: The acetal 546-3 (6.88 g, 12.95 mmol) andhydroxymethylphosphonate diethyl ester (7.76 mL, 52.65 mmol) weredissolved in 200 mL of toluene. The toluene was removed by rotaryevaporation at 70° C. under vacuum to reduce the reaction volume toapproximately 25 mL. The reaction was cooled to room temperature andp-toluene sulfonic acid monohydrate (0.490 g, 2.58 mmol) was added as asolid along with toluene (200 mL). The toluene was removed by rotaryevaporation at 70° C. under vacuum to reduce the reaction volume onceagain to approximately 25 mL. Two additional aliquots of toluene wereadded and removal by evaporation is repeated each time. The reaction wasmonitored by TLC and when completed the residue was suspended in ethylacetate (100 mL) The organic layer was washed with sodium bicarbonate(sat'd), brine and then dried over MgSO₄ (anh). The desired phosphonate547-4 was purified by column chromatography (10% to 90% EtOAc inhexane): yield 2.89 g (33%). ¹H NMR (DMSO-d₆, 300 MHz): δ 0.92 s 9H,1.25 t 6H, 2.35 t 2H, 3.84 m 4H, 4.05 m 4H, 4.32 q 1H, 5.37 t 1H; 5.62 q1H; 7.26 t 2H, 7.30-7.55 m 8H, 7.60 d 2H, 7.65 t 1H; 7.82 d 2H ppm.

Example 548 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 548-5: The silyl ether 547-4 (2.86 g, 4.57 mmol)was dissolved in a minimal amount of methanol (15 mL) and stirred a roomtemperature under nitrogen. Ammonium fluoride (1.69 g, 45.7 mmol) wasadded as a solid and the reaction was stirred at room temperature for 12hr. The reaction was monitored by TLC and, when complete the methanolwas removed under a stream of nitrogen. Add 6 mL of 1N Acetic acid (aq)and extract the aqueous phase with ethyl acetate (2×125 mL). Combine theorganic extracts and dried over Na₂SO₄(anh). The final product 548-5 waspurified by column chromatography (50% to 100% EtOAc in hexane): yield1.59 g (90%). ¹H NMR (DMSO-d₆, 300 MHz): δ 1.21 t 6H, 2.35 t 2H,3.62-3.82 m 4H, 4.05 m 4H, 4.12 q 1H; 5.30 t 1H; 5.49 q 1H; 7.47 t 2H,7.65 t 1H; 7.90 d 2H.

Example 549 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 549-6: The primary alcohol 548-5 (1.43 g, 3.69mmol) was dissolved in a 1:1 mixture of acetonitrile and water (10 mL)under nitrogen. Bisacetyliodobenzene (2.61 g, 8.12 mmol) was added as asolid along with a catalytic amount of TEMPO (0.115 g, 0.74 mmol). Thereaction was stirred at room temperature for 12 hr. and monitored byTLC. When the reaction was complete, it was frozen and lyphilized. Thecarboxylic acid 549-6 was purified by column chromatography (0% to 10%methanol in dichloromethane): yield 0.750 g (51%). ¹H NMR (CD₃CN, 300MHz): δ 1.30 t 6H, 2.45 t 2H, 3.84 m 1H, 4.00-4.20 m 5H, 4.82 d 1H; 5.50t 1H; 5.82 q 1H; 7.54 t 2H, 7.65 t 1H; 7.96 d 2H.

Example 550 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 550-7 To acid 549-6 (88 mg, 0.22 mmol) in DMF (3.1mL, 0.07 M) was added anhydrous pyridine (0.027 mL, 0.33 mmol) followedby lead tetraacetate (146 mg, 0.33 mmol). After 14 h at roomtemperature, Et₂O/H₂O (1:1, 3 mL) was added. The organics wereseparated, washed with 1 M aqueous citric acid, saturated aqueousNaHCO₃, saturated aqueous NaCl and dried over sodium sulfate. Afterremoval of solvent, the crude product 7 (50 mg, 54%) was used directlyin the next reaction.

Example 551 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 551-8: N-Acetoxy-diphenylcarbamoyl gaunine (43 mg,0.11 mmol), synthesized as described in Can. J. Chem. 65: 1436 (1987),in dichloroethane (1.1 mL, 0.1 M) was treated withN,O-bis(trimethylsilyl)acetamide (0.054 mL, 0.22 mmol). The reactionmixture was heated to 80° C. for 20 min after which the solvents wereremoved in vacuo. The crude silylated protected guanine was combinedwith phosphonate 550-7 (50 mg, 0.12 mmol) in dichloroethane (1.1 mL, 0.1M) to which TMSOTf (28 μL, 0.153 mmol) was added. The reaction mixtureheated to 60° C. for 5 h after with the reaction was quenched withsaturated aqueous NaHCO₃. The solution was extracted with CH₂Cl₂, washedwith saturated aqueous NaHCO₃, and dried over sodium sulfate. Afterremoval of solvent, the crude product was purified by columnchromatography on silica (2% MeOH/CH₂Cl₂) to provide the phosphonatediester 551-8 (18 mg, 22%). ¹H NMR (CDCl₃, 300 MHz) δ 8.30 (s, 1H), 8.15(s, 1H), 8.02 (s, 1H) 8.00 (s, 1H), 7.35-7.62 (m, 12H), 6.43 (d, 1H),6.02 (m, 1H), 5.65 (m, 1H), 4.18 (q, 4H), 3.78-4.01 (m, 2H), 2.86 (m,1H), 2.63 (m, 1H), 2.53 (s, 3H), 1.37 (t, 6H) ppm. ³¹P NMR (CDCl₃, 300MHz) δ 20.07 (s) ppm. MS (m/z): calculated 744.2 (M+H⁺). found 744.9(M+H⁺).

Example 552 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 552-9 Phosphonate ester 551-8 (14 mg, 0.02 mmol)was treated with NH₃ in MeOH (2 mL, 2.0 N) at room temperature for 9 h.After solvents were removed in vacuo, the crude product was purified bycolumn chromatography on silica (10% MeOH/CH₂Cl₂) to provide 552-9. ¹HNMR (CD₃OD, 300 MHz) δ 7.89 (s, 1H), 5.96 (d, 1H), 5.45 (m, 1H),4.10-4.21 (q, 4H), 3.84-4.02 (m, 2H), 2.92-2.47 (m, 2H), 1.33 (t, 6H)ppm. ³¹P NMR (CD₃OD, 300 MHz) δ 21.75 ppm. MS (m/z): calculated 404.1(M+H⁺). found 404.2 (M+H⁺).

Example 553 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 553-10: To phosphonate ester guanosine derivative552-9 (5.8 mg, 0.02 mmol) in anhydrous acetonitrile (0.15 mL, 0.1 M) wasadded 2,6-lutidine (0.014 mL, 0.12 mmol) followed by iodotrimethylsilane(0.016 mL, 0.12 mmol). After stirring for 15 min, triethylamine (0.12mmol) and methanol (0.020 mL) were added and solvents were removed invacuo. The crude product was purified by reverse phase columnchromatography on C18 (0-10% MeOH/H₂O-1% AcOH) to provide the phosphonicdiacid 553-10. ¹H NMR (D₂O, 300 MHz) δ 7.91 (s, 1H), 5.86 (d, 1H), 5.41(m, 1H), 3.42-3.65 (m, 2H), 2.25-2.36 (m, 2H) ppm. ³¹P NMR (D₂O, 300MHz) δ 15.16 ppm. MS (m/z): calculated 346.1 (M−H⁻). found 346.3 (M−H⁻).

Example 554 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 554-11: To phosphonic diacid 553-10 (2.5 mg, 7.2μmol) in DMF (144 μL, 0.05 M) was added tributylamine (0.0086 mL, 0.036mmol) followed by carbonyldiimidazole (12 mg, 0.072 mmol). Reaction wasstirred at room temperature for 12 h at which point MeOH (0.005 mL) wasadded and stirred for an additional 30 min. Tributyl ammoniumpyrophosphate (0.040 mg, 72 mmol) in DMF (0.16 mL) was added thereaction mixture stirred for 1 h. After the solvents were evaporated invacuo, the crude product was purified by ion exchange HPLC (0-60% TEAB)to provide the diphosphophosphonate 554-11. ¹H NMR (D₂O, 300 MHz) δ 7.94(s, 1H), 5.85 (d, 1H), 4.47 (m, 1H), 3.71-3.78 (m, 2H), 2.27-2.39 (m,2H) ppm. ³¹P NMR (D₂O, 300 MHz) δ 8.09 (d), 7.71 (s), −22.04 (t) ppm. MS(m/z): calculated 505.99 (M−H⁻). found 506.2 (M−H⁻).

Example 555 Synthesis of Exemplary Compounds of the Invention

The following Schemes 555-5 to 555-9 describes a general method ofpreparing the [3.1.0] bicyclo hexane scaffold of the Formula 555-I and555-II compounds. Exemplary structures, intermediates, substituents,protecting groups, reagents, and synthetic routes chosen for descriptionhere are meant to merely illustrate general methods of preparation, andare not intended to any way limit or denote preference to the methods.

The [3.1.0] bicyclo hexane scaffold may be synthesized by intramolecularcyclopropanation of a carbene generated by decomposition of a diazo1,3-ketoester (Moon et al (2000) Organic Letters 2(24):3793-3796). Therequisite 1,3-ketoester 555-5.1 may be prepared from acetoacetate esteranion addition to ene-aldehydes, e.g. acrolein (Scheme 555-5a). Forexample, ethyl acetoacetate treated with 2 equivalents of lithiumdiisopropylamide at −78° C. and then one equivalent of acrolein givesthe 1,3-ketoester 555-5.1 (Yoshimura et al (2002) Jour. Org. Chem.67:5938-5945). Protection of the hydroxyl may be accomplished withphenyldimethylsilyl chloride to give 555-5.2 where PG isphenyldimethylsilyl (PhMe₂Si—). Other trialkylsilyl protecting groupsmay be useful. Diazotization with p-toluenesulfonyl azide gives 555-5.3.Treatment of 555-5.3 with a carbenoid insertion catalyst, e.g. CuSO₄ orRh(OAc)₂, gives 555-5.4 as a mixture of diastereomers.

The ester of 555-5.4 may be hydrolyzed to the hydroxymethyl 555-5.5 orsaponified directly to carboxylic acid 555-5.6 (Scheme 555-5b).Appropriate oxidant(s) can convert the primary alcohol 555-5.5 tocarboxylic acid 555-5.6 or its corresponding ester. In the case of anester, an additional deprotection step will give the carboxylic acid,555-5.6. A variety of oxidation procedures exist in the literature andcan be utilized here. These include but are not limited to the followingmethods: (i) pyridinium dichromate in Ac₂O, t-BuOH, and dichloromethaneproducing the t-butyl ester, followed by a deprotection using reagentsuch as trifluoroacetic acid to convert the ester to the correspondingcarboxylic acid (see Classon, et al, Acta Chem. Scand. Ser. B; 39; 1985;501-504. Cristalli, et al; J. Med. Chem.; 31; 1988; 1179-1183.); (ii)iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, freeradical (TEMPO) in acetonitrile, producing the carboxylic acid (See Epp,et al; J. Org. Chem. 64; 1999; 293-295. Jung et al; J. Org. Chem.; 66;2001; 2624-2635.); (iii) sodium periodate, ruthenium(III) chloride inchloroform producing the carboxylic acid (see Kim, et al, J. Med. Chem.37; 1994; 4020-4030. Homma, et al; J. Med. Chem.; 35; 1992; 2881-2890);(iv) chromium trioxide in acetic acid producing the carboxylic acid (seeOlsson et al; J. Med. Chem.; 29; 1986; 1683-1689. Gallo-Rodriguez et al;J. Med. Chem.; 37; 1994; 636-646); (v) potassium permanganate in aqueouspotassium hydroxide producing the carboxylic acid (see Ha, et al; J.Med. Chem.; 29; 1986; 1683-1689. Franchetti, et al; J. Med. Chem.; 41;1998; 1.708-1715.) (vi) nucleoside oxidase from S. maltophilia to givethe carboxylic acid (see Mahmoudian, et al; Tetrahedron; 54; 1998;8171-8182.)

Carboxylic acid 555-5.6 may be converted by decarboxylation to acetate555-5.7 using lead(IV) tetraacetate (Teng et al; (1994) J. Org. Chem.;59:278-280; Schultz, et al; J. Org. Chem.; 48; 1983; 3408-3412. Whenlead(IV) tetraacetate is used together with lithium chloride (see Kochi,et al; J. Am. Chem. Soc.; 87; 1965; 2052), the corresponding chloride isobtained 555-5.8. Lead(IV) tetraacetate in combination withN-chlorosuccinimide can also produce 555-5.8 (Wang, et al; Tet. Asym.;1; 1990; 527 and Wilson et al; Tet. Asym.; 1; 1990; 525). Alternatively,the acetate can also be converted to other leaving groups such asbromide by treatment of trimethylsilyl bromide (Spencer, et al; J. Org.Chem.; 64; 1999; 3987-3995).

Intermediates 555-5.7 and 555-5.8 may react with a variety ofnucleophiles as described by Teng et al; Synlett; 1996; 346-348 and U.S.Pat. No. 6,087,482; Column 54 line 64 to Column 55 line 20.Specifically, 555-5.7 may be reacted with diethylhydroxymethylphosphonate in the presence of trimethylsilyltrifluoromethanesulfonate (TMS-OTf) to give 555-5.9 (Scheme 555-5c). Itcan be envisioned that other compounds with the general structure ofHO-linker-POR^(P1)R^(P2) can also be used so long as the functionalgroups in these compounds are compatible with the coupling reactionconditions. There are many examples in the published literaturedescribing the coupling of 1′ acetyl furanosyl compounds with a varietyof alcohols. The reactions can be facilitated with a number of reagents,such as silver(I) salts (see Kim et al (1991) J. Org. Chem.56:2642-2647, Toikka et al (1999) J. Chem. Soc. Perkins Trans. 1;13:1877-1884); mercury(II) salts (see Veeneman et al (1987) Recl. Trav.Chim. Pays-Bas; 106:129-131); boron trifluoride diethyl etherate (seeKunz et al (1985) Hel. Chim Acta; 68:283-287); tin(II) chloride (seeO'Leary et al (1994) J. Org. Chem. 59:6629-6636); alkoxide (seeShortnacy-Fowler et al (2001) Nucleosides & Nucleotides; 20:1583-1598);and iodine (see Kartha et al (2001) J. Chem. Soc. Perkins Trans. 1770-772). These methods can be selectively used in conjunction withdifferent methods in forming intermediates from 555-5.6 with variousleaving groups (LG).

The introduction and removal of protecting groups (represented in thestructures herein as PG) from a compound is common practice art inorganic synthesis. Many sources of information of the art are availablein the published literature, e.g. Greene and Wuts, Protecting Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, Inc., 1999. The mainpurpose is to temporarily transform a functional group and mask itsreactivity so that it will survive a set of subsequent reactionprocedures. Afterwards, the original functional group can be restored bya preconceived deprotection procedure. Therefore, the transformations inSchemes 555-(5a-c) are intended to build the [3.1.0] scaffold with theappropriate latent functionality or reactivity components.

The keto group of certain intermediates, e.g. 555-5.4 may be elaboratedto ribofuranose-type analogs 555-6.1 where Z¹ are for example, eachhydroxyl or protected hydroxyl (Scheme 555-6). The hydroxyl groups canbe protected as benzoyl (Bz) esters to give 555-6.2. The bridgeheadcarboxylate ester can then be orthogonally hydrolyzed to give 555-6.3 orreduced to hydroxymethyl 555-6.4. Oxidation of 555-6.4, e.g. usingiodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, freeradical (TEMPO), converts the primary alcohol to the corresponding acid555-6.3. Further oxidation of 555-6.3 using lead tetraacetate canproduce acetate 555-6.5. Coupling between 555-6.5 and hydroxyalkyldialkylphosphonate compounds, e.g. diethyl hydroxymethylphosphonate(available from Sigma-Aldrich, Cat. No. 39, 262-6) and TMS-OTf canafford 555-6.6. Treating 555-6.6 with TMS—Br converts the phosphodiesterto the corresponding phosphonic acid 555-6.7. Deprotection, e.g. NH₃ inmethanol, of the 2′- and 3′-hydroxyl gives 555-6.8.

The phosphonic acids in 555-(6.6-6.8) are used as examples forillustration purpose. Other forms of phosphonates can be accessed viathe phosphonic acid, or other forms, such as the corresponding diesters.See Schemes 555-A and 555-(1-4) for exemplary interconversions ofphosphonate moieties.

Compounds such as 555-6.6 can be further elaborated by selectivedeprotection of PG and introduction of the nucleobase moiety (B). Forexample, where PG is trialkylsilyl, e.g. triethylsilyl,t-butyldimethylsilyl, or phenyldimethylsilyl, treatment of 555-6.6 witha fluoride reagent, e.g. tetrabutylammonium fluoride in THF, mayselectively remove PG. The resulting hydroxyl may be converted to aleaving group (LG) such as chloro or acetate 555-7.1 underVorbruggen-type reaction conditions, or the hydroxyl 555-7.2 reacted insitu, e.g. Mitsunobu conditions, to establish the carbon-nitrogen bondwith a nucleobase or protected nucleobase reagent to give 555-7.3(Scheme 555-7). Suitable nucleobase or protected nucleobase reagents (B)include thymidine, cytosine, adenine, guanine, and silylated formsthereof. The resulting covalent attachment may be 9-purinyl or1-pyrimidinyl. Other positional isomers may result and conventionalmeans of separation may be employed to generate pure 555-7.3 compounds.The 2′ and 3′ protecting groups (Bz=benzoyl) may be removed fromintermediate 555-7.3 with aqueous base to give 555-7.4. The ethyl groupsof 555-7.4 may be removed with a dealkylation reagent such astrimethylsilyl bromide to give phosphonic acid 555-7.5 which may befurther elaborated according to the reactions shown in Schemes 555-A and1-4 to other phosphonate moieties, including diphosphophosphonate andphosphophosphonate compounds.

Scheme 555-8 shows an exemplary route to 2′-β-methyl, 2′-3′ hydroxylbicylco adenine compounds. The 3′ and 5′ hydroxyl groups of [3.1.0]bicyclo analog of adenosine 555-8.1 (Kim, et al (2002) J. Med. Chem.45:208-218) may be selectively silylated to give 555-8.2. The 2′hydroxyl group may be oxidized under Dess-Martin periodinane conditionsto give 555-8.3. The 2′ keto of 555-8.3 may be methylenated with aWittig reagent and desilylated to give 555-8.4. Epoxidation of 555-8.4gives 555-8.5. Hydride attack on the methylene carbon of the epoxide555-8.5 gives 555-8.6 with the 2′,3′-α-dihydroxy, 2′-β-methyl motif.This synthetic route may be versatile in the preparation of a variety of2′,3′-a-dihydroxy, 2′-β-methyl[3.1.0] bicyclo compounds where B=anyprotected or unprotected nucleobase.

The 5′ hydroxymethyl group of 2′,3′-α-dihydroxy,2′-β-methyl[3.1.0]bicyclo compounds, e.g. 555-8.6, may be elaborated byselective reactions such as those shown in Scheme 555-9. The 5′ carbonmay be removed by an oxidative decarboxylation to allow attachment of aphosphonate moiety through an oxygen atom bound directly to the [3.1.0]scaffold. The 5′ hydroxyl group of 555-8.6 may be selectively protectedas the 5′ tert-butyldiphenylsilyl ether (TBDPS) and then the 2′ and 3′hydroxyls may be protected as methoxymethyl ethers to give 555-9.1. The5′ TBDPSi group may be removed with tetra-butyl ammonium fluoride (TBAF)and the resulting hydroxymethyll oxidized with the periodinane reagent,Phl(OAc)₂ and TEMPO to the carboxylic acid 555-9.2. Oxidativedecarboxylation of 555-9.2 with lead tetracetate and treatment withlithium hydroxide gives 555-9.3. Alkylation of the hydroxyl of 555-9.3with bromomethyldiethyl phosphonate gives 555-9.4. The phosphonate ethylgroups and the 2′, 3′ methoxymethyl (MOM) protecting groups may beremoved with iodotrimethylsilane to give 555-9.5. The phosphonic acidgroup of 555-9.5 may be activated, for example with carbonyldiimidazole(CDI) and reacted with pyrophosphate anion to give diphosphophosphonate555-9.6. Other phosphonic acid conversions may be conducted, asdescribed in Schemes 555-A and 555(1-4).

Intermediate 555-8.2 is versatile for the preparation of 2′hydroxyl[3.1.0] bicyclo compounds (Scheme 555-10). Protection of the 2′hydroxyl with para-methoxybenzyl bromide and silyl removal with TBAFgives 555-10.1. The 5′ hydroxyl is protected with the TBDPSi group togive 555-10.2. The 3′ thioester of 555-10.2 is formed with phenylchlorothionoformate followed by reduction with tributyl tin hydride withAIBN to give 555-10.3. Desilyation with TBAF and oxidation with BAIB andTEMPO furnishes the carboxylic acid 555-10.4.

Oxidative decarboxylation of 555-10.4 with lead tetracetate followed bylithium hydroxide treatment gives the hydroxyl 555-11.1 (Scheme 555-11).Alkylation of hydroxyl 555-11.1 with bromomethyl diethyl phosphonategives 555-11.2. Iodotrimethylsilane cleaves the ethyl groups from thediethylphosphonate and ceric ammonium nitrate deprotects thepara-methoxy benzyl group of 555-11.2 to give 555-11.3. Phosphonateactivation with CDI and addition of pyrophosphate gives the 2′-hydroxydiphosphophosphonate[3.1.0] compound 555-11.4.

Example 556 Synthesis of Exemplary Compounds of the Invention

The following Schemes describe the general method of preparing the 2′fluoro, 2′-3′ didehydro nucleosidescaffold of compounds of the presentinvention.

Methods of introduction of fluorine at the 2′ position ofribonucleosides and nucleoside analogs are described in U.S. Pat. No.5,824,793; U.S. Pat. No. 5,859,233; Choo, H. et al Journal of MedicinalChemistry (2003), 46(3), 389-398; Moon, H. et al Journal of the ChemicalSociety, Perkin Transactions 1 (2002), (15), 1800-1804; Lee, Kyeong;Choi, Y. et al Journal of Medicinal Chemistry (2002), 45(6), 1313-1320;Lee, Kyeong; Choi, Yongseok; Hong, J. et al Nucleosides & Nucleotides(1999), 18(4 & 5), 537-540; Lee, K. et al Journal of Medicinal Chemistry(1999), 42(7), 1320-1328; Choi, Y. et al Tetrahedron Letters (1998),39(25), 4437-4440; Chen, Shu-Hui et al Bioorganic & Medicinal ChemistryLetters (1998), 8(13), 1589-1594; Siddiqui, Maqbool et al TetrahedronLetters (1998), 39(13), 1657-1660; Nakayama, Toshiaki et al NucleicAcids Symposium Series (1991), 25 (Symp. Nucleic Acids Chem., 18th,1991), 191-2; Huang, Jai Tung et al Journal of Medicinal Chemistry(1991), 34(5), 1640-6; Sterzycki, Roman Z et al Journal of MedicinalChemistry (1990), 33(8), 2150-7; Martin, Joseph A et al Journal ofMedicinal Chemistry (1990), 33(8), 2137-45; Watanabe, Kyoichi et alJournal of Medicinal Chemistry (1990), 33(8), 2145-50; Zemlicka et alJournal of the American Chemical Society (1972) 94(9):3213-3218.

Schemes 556 (A-F) show the synthetic routes which have been utilized toprepare the exemplary embodiments shown therein.

The (−) enantiomer of adenosine 556-A.1 was tritylated at the N-6 of theadenine exocyclic amine and the 5′ hydroxyl with an excess of trityl(Tr, triphenylmethyl, Ph₃C—) chloride with dimethylaminopyridine inpyridine to give bis-trityl 556-A.2 which was treated with triflicanhydride in dichloromethane and DMAP to give 556-A.3 (Scheme 556-A).The 2′ triflate group was displaced by fluoride with tetra-butylammoniumfluoride in THF at room temperature to give 556-A.4.

Example 600

By way of example and not limitation, embodiments of the invention arenamed below in tabular format (Table 100). These embodiments are of thegeneral formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formula I-336 herein, wherein A⁰ is the point of covalentattachment of Sc to Lg, as well as in Tables 1.1 to 1.5 below. For thoseembodiments described in Table 100, Sc is a nucleus designated by anumber and each substituent is designated in order by letter or number.Tables 1.1 to 1.5 are a schedule of nuclei used in forming theembodiments of Table 100. Each nucleus (Sc) is given a numberdesignation from Tables 1.1 to 1.5, and this designation appears firstin each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to20.36 list the selected linking groups (Lg) and prodrug (Pd¹ and Pd²)substituents, again by letter or number designation, respectively.Accordingly, a compound of the formula MBF includes compounds having Scgroups based on formula 1-336 herein as well as compounds according toTable 100 below. In all cases, compounds of the formula MBF have groupsLg, Pd¹ and Pd² setforth in the Tables below.

Accordingly, each named embodiment of Table 100 is depicted by a numberdesignating the nucleus from Table 1.1-1.5, followed by a letterdesignating the linking group (Lg) from Table 10.1-10.19, and twonumbers designating the two prodrug groups (Pd¹ and Pd²) from Table20.1-20.36. In graphical tabular form, each embodiment of Table 100appears as a name having the syntax:

Sc.Lg.Pd¹.Pd²

Each Sc group is shown having a tilda (“{tilde over ( )}”). The tilda isthe point of covalent attachment of Sc to Lg. Q¹ and Q² of the linkinggroups (Lg), it should be understood, do not represent groups or atomsbut are simply connectivity designations. Q¹ is the site of the covalentbond to the nucleus (Sc) and Q² is the site of the covalent bond to thephosphorous atom of formula MBF. Each prodrug group (Pd¹ and Pd²) arecovalently bonded to the phosphorous atom of MBF at the tilda symbol(“1”). Some embodiments of Tables 10.1-10.19 and 20.1-20.36 may bedesignated as a combination of letters and numbers (Table 10.1-10.19) ornumber and letter (Table 20.1-20.36). For example there are Table 10entries for BJ1 and BJ2. In any event, entries of Table 10.1-10.19always begin with a letter and those of Table 20.1-20.36 always beginwith a number. When a nucleus (Sc) is shown enclosed within squarebrackets (“[ ]”) and a covalent bond extends outside the brackets, thepoint of covalent attachment of Sc to Lg may be at any substitutablesite on SC. Selection of the point of attachment is described herein. Byway of example and not limitation, the point of attachment is selectedfrom those depicted in the schemes and examples.

TABLE 1.1

TABLE 1.2

TABLE 1.3

TABLE 1.4

TABLE 1.5

TABLE 10.1

TABLE 10.2

TABLE 10.3

TABLE 10.4

TABLE 10.5

TABLE 10.6

TABLE 10.7

TABLE 10.8

TABLE 10.9

TABLE 10.10

TABLE 10.11

TABLE 10.12

TABLE 10.13

TABLE 10.14

TABLE 10.15

TABLE 10.16

TABLE 10.17

TABLE 10.18

TABLE 10.19

TABLE 20.1

TABLE 20.2

TABLE 20.3

TABLE 20.4

TABLE 20.5

TABLE 20.6

TABLE 20.7

TABLE 20.8 42

43

44

45

46

47

48

49

TABLE 20.9 50

51

52

53

54

55

56

57

TABLE 20.10 58

59

60

TABLE 20.11 61

62

63

64

65

66

67

68

TABLE 20.12 69

70

71

TABLE 20.13 72

73

74

75

76

77

78

79

TABLE 20.14 80

81

82

TABLE 20.15 83

84

85

86

87

88

89

90

TABLE 20.16 91

92

93

94

95

96

97

98

TABLE 20.17 99

100

101

102

103

104

105

106

TABLE 20.18 107

108

109

TABLE 20.19 110

111

112

113

114

115

116

117

TABLE 20.20 118

119

120

TABLE 20.21 121

122

123

124

125

126

127

128

TABLE 20.22 129

130

131

TABLE 20.23 132

133

134

135

136

137

138

139

TABLE 20.24 140

141

142

143

144

145

146

147

TABLE 20.25 148

149

150

151

152

153

154

155

156

157

158

159

TABLE 20.26 160

161

162

163

164

165

166

167

168

169

170

171

TABLE 20.27 172

173

174

175

176

177

178

179

TABLE 20.28 180

181

182

183

184

185

TABLE 20.29 186

187

188

189

190

191

192

193

TABLE 20.30 194

195

196

197

198

199

TABLE 20.31 200

201

202

203

204

205

206

207

TABLE 20.32 208

209

210

211

212

213

TABLE 20.33 214

215

216

217

218

219

220

221

TABLE 20.34 222

223

224

225

226

227

TABLE 20.35 228

229

230

231

232

233

234

235

TABLE 20.36 236

237

238

239

240

241

242

243

TABLE 20.37 244

245

246

247

TABLE 100 Prodrugs of 1.B 1.B.228.228; 1.B.228.229; 1.B.228.230;1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239;1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172;1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238;1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169;1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228;1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237;1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166;1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236;1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157;1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240;1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230; 1.B.236.231;1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154;1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230;1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239;1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172;1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229;1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238;1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228;1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237;1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166;1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244;1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236;1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240;1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231;1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154;1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175;1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229; 1.B.166.230;1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172;1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229;1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237; 1.B.169.238;1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166; 1.B.169.169;1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244; 1.B.172.228;1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166;1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244;1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236;1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157;1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240;1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154;1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175;1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230;1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239;1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172;1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D 1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237;1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166;1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240; 1.D.228.244;1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236;1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157;1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231;1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154;1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175;1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229; 1.D.231.230;1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239;1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229;1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238;1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169;1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228;1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237;1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244;1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236;1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157;1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240;1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231;1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175;1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230;1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239;1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172;1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D.157.229;1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169;1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228;1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237;1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166;1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244;1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157;1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240;1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230; 1.D.172.231;1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154;1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175;1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239;1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172;1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228; 1.D.240.229;1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237; 1.D.240.238;1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166; 1.D.240.169;1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228;1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237;1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166;1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240; 1.D.244.244;Prodrugs of 1.E 1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231;1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239; 1.E.228.154;1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172; 1.E.228.175;1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229; 1.E.229.230;1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239;1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172;1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229;1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 1.E.230.238;1.E.230.239; 1.E.230.154; 1.E.230.157; 1.E.230.166; 1.E.230.169;1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244; 1.E.231.228;1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237;1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1.E.231.166;1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244;1.E.236.228; 1.E.236.229; 1.E.236.230; 1.E.236.231; 1.E.236.236;1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154; 1.E.236.157;1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175; 1.E.236.240;1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230; 1.E.237.231;1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239; 1.E.237.154;1.E.237.157; 1.E.237.166; 1.E.237.169; 1.E.237.172; 1.E.237.175;1.E.237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229; 1.E.238.230;1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238; 1.E.238.239;1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169; 1.E.238.172;1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228; 1.E.239.229;1.E.239.230; 1.E.239.231; 1.E.239.236; 1.E.239.237; 1.E.239.238;1.E.239.239; 1.E.239.154; 1.E.239.157; 1.E.239.166; 1.E.239.169;1.E.239.172; 1.E.239.175; 1.E.239.240; 1.E.239.244; 1.E.154.228;1.E.154.229; 1.E.154.230; 1.E.154.231; 1.E.154.236; 1.E.154.237;1.E.154.238; 1.E.154.239; 1.E.154.154; 1.E.154.157; 1.E.154.166;1.E.154.169; 1.E.154.172; 1.E.154.175; 1.E.154.240; 1.E.154.244;1.E.157.228; 1.E.157.229; 1.E.157.230; 1.E.157.231; 1.E.157.236;1.E.157.237; 1.E.157.238; 1.E.157.239; 1.E.157.154; 1.E.157.157;1.E.157.166; 1.E.157.169; 1.E.157.172; 1.E.157.175; 1.E.157.240;1.E.157.244; 1.E.166.228; 1.E.166.229; 1.E.166.230; 1.E.166.231;1.E.166.236; 1.E.166.237; 1.E.166.238; 1.E.166.239; 1.E.166.154;1.E.166.157; 1.E.166.166; 1.E.166.169; 1.E.166.172; 1.E.166.175;1.E.166.240; 1.E.166.244; 1.E.169.228; 1.E.169.229; 1.E.169.230;1.E.169.231; 1.E.169.236; 1.E.169.237; 1.E.169.238; 1.E.169.239;1.E.169.154; 1.E.169.157; 1.E.169.166; 1.E.169.169; 1.E.169.172;1.E.169.175; 1.E.169.240; 1.E.169.244; 1.E.172.228; 1.E.172.229;1.E.172.230; 1.E.172.231; 1.E.172.236; 1.E.172.237; 1.E.172.238;1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166; 1.E.172.169;1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244; 1.E.175.228;1.E.175.229; 1.E.175.230; 1.E.175.231; 1.E.175.236; 1.E.175.237;1.E.175.238; 1.E.175.239; 1.E.175.154; 1.E.175.157; 1.E.175.166;1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240; 1.E.175.244;1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231; 1.E.240.236;1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154; 1.E.240.157;1.E.240.166; 1.E.240.169; 1.E.240.172; 1.E.240.175; 1.E.240.240;1.E.240.244; 1.E.244.228; 1.E.244.229; 1.E.244.230; 1.E.244.231;1.E.244.236; 1.E.244.237; 1.E.244.238; 1.E.244.239; 1.E.244.154;1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172; 1.E.244.175;1.E.244.240; 1.E.244.244; Prodrugs of 1.G 1.G.228.228; 1.G.228.229;1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237; 1.G.228.238;1.G.228.239; 1.G.228.154; 1.G.228.157; 1.G.228.166; 1.G.228.169;1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244; 1.G.229.228;1.G.229.229; 1.G.229.230; 1.G.229.231; 1.G.229.236; 1.G.229.237;1.G.229.238; 1.G.229.239; 1.G.229.154; 1.G.229.157; 1.G.229.166;1.G.229.169; 1.G.229.172; 1.G.229.175; 1.G.229.240; 1.G.229.244;1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231; 1.G.230.236;1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154; 1.G.230.157;1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175; 1.G.230.240;1.G.230.244; 1.G.231.228; 1.G.231.229; 1.G.231.230; 1.G.231.231;1.G.231.236; 1.G.231.237; 1.G.231.238; 1.G.231.239; 1.G.231.154;1.G.231.157; 1.G.231.166; 1.G.231.169; 1.G.231.172; 1.G.231.175;1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G.236.229; 1.G.236.230;1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238; 1.G.236.239;1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169; 1.G.236.172;1.G.236.175; 1.G.236.240; 1.G.236.244; 1.G.237.228; 1.G.237.229;1.G.237.230; 1.G.237.231; 1.G.237.236; 1.G.237.237; 1.G.237.238;1.G.237.239; 1.G.237.154; 1.G.237.157; 1.G.237.166; 1.G.237.169;1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244; 1.G.238.228;1.G.238.229; 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1.G.169.230; 1.G.169.231; 1.G.169.236; 1.G.169.237;1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157; 1.G.169.166;1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244;1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236;1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157;1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175; 1.G.172.240;1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230; 1.G.175.231;1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239; 1.G.175.154;1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175;1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230;1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239;1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169; 1.G.240.172;1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228; 1.G.244.229;1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237; 1.G.244.238;1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169;1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244; Prodrugs of 1.I1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236;1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157;1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175; 1.I.228.240;1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230; 1.I.229.231;1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239; 1.I.229.154;1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175;1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230;1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238; 1.I.230.239;1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169; 1.I.230.172;1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228; 1.I.231.229;1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238;1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169;1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228;1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236; 1.I.236.237;1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157; 1.I.236.166;1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240; 1.I.236.244;1.I.237.228; 1.I.237.229; 1.I.237.230; 1.I.237.231; 1.I.237.236;1.I.237.237; 1.I.237.238; 1.I.237.239; 1.I.237.154; 1.I.237.157;1.I.237.166; 1.I.237.169; 1.I.237.172; 1.I.237.175; 1.I.237.240;1.I.237.244; 1.I.238.228; 1.I.238.229; 1.I.238.230; 1.I.238.231;1.I.238.236; 1.I.238.237; 1.I.238.238; 1.I.238.239; 1.I.238.154;1.I.238.157; 1.I.238.166; 1.I.238.169; 1.I.238.172; 1.I.238.175;1.I.238.240; 1.I.238.244; 1.I.239.228; 1.I.239.229; 1.I.239.230;1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238; 1.I.239.239;1.I.239.154; 1.I.239.157; 1.I.239.166; 1.I.239.169; 1.I.239.172;1.I.239.175; 1.I.239.240; 1.I.239.244; 1.I.154.228; 1.I.154.229;1.I.154.230; 1.I.154.231; 1.I.154.236; 1.I.154.237; 1.I.154.238;1.I.154.239; 1.I.154.154; 1.I.154.157; 1.I.154.166; 1.I.154.169;1.I.154.172; 1.I.154.175; 1.I.154.240; 1.I.154.244; 1.I.157.228;1.I.157.229; 1.I.157.230; 1.I.157.231; 1.I.157.236; 1.I.157.237;1.I.157.238; 1.I.157.239; 1.I.157.154; 1.I.157.157; 1.I.157.166;1.I.157.169; 1.I.157.172; 1.I.157.175; 1.I.157.240; 1.I.157.244;1.I.166.228; 1.I.166.229; 1.I.166.230; 1.I.166.231; 1.I.166.236;1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154; 1.I.166.157;1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240;1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231;1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154;1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175;1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230;1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239;1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229;1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238;1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169;1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228;1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237;1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244;1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240;1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230; 1.J.236.231;1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175;1.J.236.240; 1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230;1.J.237.231; 1.J.237.236; 1.J.237.237; 1.J.237.238; 1.J.237.239;1.J.237.154; 1.J.237.157; 1.J.237.166; 1.J.237.169; 1.J.237.172;1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229;1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169;1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228;1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237;1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166;1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236;1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157;1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240;1.J.154.244; 1.J.157.228; 1.J.157.229; 1.J.157.230; 1.J.157.231;1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154;1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230;1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239;1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172;1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J.169.228; 1.J.169.229;1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237; 1.J.169.238;1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228;1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237;1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166;1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244;1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236;1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240;1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;1.L.230.157; 1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175;1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L.231.229; 1.L.231.230;1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239;1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172;1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238;1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169;1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L.236.244; 1.L.237.228;1.L.237.229; 1.L.237.230; 1.L.237.231; 1.L.237.236; 1.L.237.237;1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157; 1.L.237.166;1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236;1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157;1.L.238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240;1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231;1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154;1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154;1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230;2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229;2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238;2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169;2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228;2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237;2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166;2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244;2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236;2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157;2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240;2.E.244.244; Prodrugs of 2.G 2.G.228.228; 2.G.228.229; 2.G.228.230;2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239;2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172;2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229;2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238;2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169;2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228;2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237;2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166;2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244;2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236;2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157;2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240;2.G.231.244; 2.G.236.228; 2.G.236.229; 2.G.236.230; 2.G.236.231;2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154;2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175;2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230;2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239;2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172;2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229;2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238;2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169;2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228;2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237;2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166;2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244;2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236;2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157;2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240;2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231;2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154;2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175;2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230;2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239;2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172;2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229;2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238;2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169;2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228;2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237;2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166;2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244;2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236;2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157;2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240;2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231;2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154;2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175;2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230;2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239;2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172;2.G.244.175; 2.G.244.240; 2.G.244.244; Prodrugs of 2.I 2.I.228.228;2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237;2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166;2.I.228.169; 2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244;2.I.229.228; 2.I.229.229; 2.I.229.230; 2.I.229.231; 2.I.229.236;2.I.229.237; 2.I.229.238; 2.I.229.239; 2.I.229.154; 2.I.229.157;2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175; 2.I.229.240;2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231;2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154;2.I.230.157; 2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175;2.I.230.240; 2.I.230.244; 2.I.231.228; 2.I.231.229; 2.I.231.230;2.I.231.231; 2.I.231.236; 2.I.231.237; 2.I.231.238; 2.I.231.239;2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169; 2.I.231.172;2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229;2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238;2.I.236.239; 2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169;2.I.236.172; 2.I.236.175; 2.I.236.240; 2.I.236.244; 2.I.237.228;2.I.237.229; 2.I.237.230; 2.I.237.231; 2.I.237.236; 2.I.237.237;2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157; 2.I.237.166;2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244;2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236;2.I.238.237; 2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157;2.I.238.166; 2.I.238.169; 2.I.238.172; 2.I.238.175; 2.I.238.240;2.I.238.244; 2.I.239.228; 2.I.239.229; 2.I.239.230; 2.I.239.231;2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239; 2.I.239.154;2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175;2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230;2.I.154.231; 2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239;2.I.154.154; 2.I.154.157; 2.I.154.166; 2.I.154.169; 2.I.154.172;2.I.154.175; 2.I.154.240; 2.I.154.244; 2.I.157.228; 2.I.157.229;2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237; 2.I.157.238;2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169;2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228;2.I.166.229; 2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237;2.I.166.238; 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2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239;2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172;2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229;2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169;2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244; Prodrugs of 2.O2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236;2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157;2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240;2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231;2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154;2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175;2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230;2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239;2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172;2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229;2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238;2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169;2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228;2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237;2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166;2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244;2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236;2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157;2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240;2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231;2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154;2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175;2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230;2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172;2.O.239.175; 2.O.239.240; 2.O.239.244; 2.O.154.228; 2.O.154.229;2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238;2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169;2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228;2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237;2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166;2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244;2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236;2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157;2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231;2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154;2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175;2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230;2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239;2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229;2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238;2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169;2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228;2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237;2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244;2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236;2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157;2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240;2.O.244.244; Prodrugs of 2.P 2.P.228.228; 2.P.228.229; 2.P.228.230;2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239;2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172;2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238;2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169;2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228;2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237;2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166;2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236;2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157;2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240;2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231;2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154;2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230;2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239;2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172;2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229;2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238;2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228;2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237;2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166;2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244;2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236;2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240;2.P.154.244; 2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231;2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154;2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175;2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230;2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172;2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229;2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238;2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169;2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228;2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166;2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244;2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236;2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157;2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240;2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154;2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175;2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230;2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239;2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172;2.P.244.175; 2.P.244.240; 2.P.244.244; Prodrugs of 2.U 2.U.228.228;2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166;2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244;2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236;2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157;2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240;2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154;2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175;2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230;2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239;2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172;2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238;2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169;2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228;2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237;2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166;2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236;2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157;2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240;2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231;2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154;2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230;2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239;2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172;2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229;2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238;2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228;2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237;2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166;2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244;2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236;2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240;2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231;2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154;2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175;2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230;2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172;2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229;2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238;2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169;2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228;2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166;2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;Prodrugs of 2.W 2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231;2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154;2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175;2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230;2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172;2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229;2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238;2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169;2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228;2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166;2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244;2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236;2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157;2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240;2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154;2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175;2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230;2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239;2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172;2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238;2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169;2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228;2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237;2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244;2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236;2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157;2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240;2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231;2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175;2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230;2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239;2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172;2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229;2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169;2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228;2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237;2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166;2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244;2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157;2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240;2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231;2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154;2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175;2.W.244.240; 2.W.244.244; Prodrugs of 2.Y 2.Y.228.228; 2.Y.228.229;2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238;2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228;2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237;2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166;2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244;2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236;2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240;2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231;2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154;2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175;2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230;2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172;2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229;2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238;2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169;2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228;2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166;2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244;2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236;2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157;2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240;2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154;2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175;2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230;2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239;2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172;2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238;2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169;2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228;2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237;2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166;2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236;2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157;2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240;2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231;2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154;2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230;2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239;2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172;2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229;2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238;2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244; Prodrugs of 3.B3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236;3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157;3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240;3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231;3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154;3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230;3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239;3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172;3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229;3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238;3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228;3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237;3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166;3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244;3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236;3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240;3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231;3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154;3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175;3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230;3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172;3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229;3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238;3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169;3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228;3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166;3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244;3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236;3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157;3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240;3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154;3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175;3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230;3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239;3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172;3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238;3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169;3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228;3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237;3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166;3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236;3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157;3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240;3.B.244.244; Prodrugs of 3.D 3.D.228.228; 3.D.228.229; 3.D.228.230;3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239;3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172;3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238;3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169;3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228;3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237;3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166;3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236;3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157;3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240;3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231;3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154;3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230;3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239;3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172;3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229;3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238;3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169;3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228;3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237;3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166;3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244;3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157;3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240;3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231;3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154;3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175;3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239;3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172;3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229;3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238;3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166; 3.D.169.169;3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237;3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166;3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244;3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236;3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157;3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231;3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154;3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175;3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230;3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239;3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244; Prodrugs of 3.E 3.E.228.228;3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166;3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244;3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236;3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157;3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240;3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154;3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175;3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230;3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239;3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172;3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238;3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169;3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228;3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237;3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166;3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236;3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157;3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240;3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231;3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154;3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230;3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239;3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172;3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229;3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238;3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228;3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237;3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166;3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244;3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157;3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240;3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231;3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154;3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175;3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239;3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172;3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229;3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238;3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169;3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237;3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166;3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;Prodrugs of 3.G 3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231;3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154;3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175;3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230;3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172;3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229;3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238;3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169;3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228;3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166;3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244;3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236;3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157;3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240;3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154;3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175;3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230;3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239;3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172;3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238;3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169;3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228;3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237;3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166;3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236;3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157;3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240;3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231;3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154;3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230;3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239;3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172;3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229;3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238;3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228;3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237;3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166;3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244;3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236;3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240;3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231;3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154;3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175;3.G.244.240; 3.G.244.244; Prodrugs of 3.I 3.I.228.228; 3.I.228.229;3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169;3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228;3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237;3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166;3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244;3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157;3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240;3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231;3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154;3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175;3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239;3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172;3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229;3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238;3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169;3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237;3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166;3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244;3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236;3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157;3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231;3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154;3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175;3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230;3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239;3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229;3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238;3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169;3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228;3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237;3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244;3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236;3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157;3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240;3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231;3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175;3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230;3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239;3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172;3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229;3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169;3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244; Prodrugs of 3.J3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236;3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157;3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240;3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231;3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154;3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230;3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239;3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172;3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J.231.229;3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238;3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228;3.J.236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237;3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166;3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244;3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231; 3.J.237.236;3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240;3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231;3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154;3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175;3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230;3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172;3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229;3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238;3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169;3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228;3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166;3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244;3.J.166.228; 3.J.166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236;3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157;3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231;3.J.169.236; 3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154;3.J.169.157; 3.J.169.166; 3.J.169.169; 3.J.169.172; 3.J.169.175;3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230;3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239;3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229;3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238;3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169;3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228;3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237;3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244;3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236;3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157;3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240;3.J.244.244; Prodrugs of 3.L 3.L.228.228; 3.L.228.229; 3.L.228.230;3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239;3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172;3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238;3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169;3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228;3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237;3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166;3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236;3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157;3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240;3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231;3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154;3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230;3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239;3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172;3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229;3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238;3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228;3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237;3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166;3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244;3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236;3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240;3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231;3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154;3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175;3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230;3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172;3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229;3.L.169.230; 3.L.169.231; 3.L.169.236; 3.L.169.237; 3.L.169.238;3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169;3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228;3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166;3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244;3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236;3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157;3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240;3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154;3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175;3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230;3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239;3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172;3.L.244.175; 3.L.244.240; 3.L.244.244; Prodrugs of 3.O 3.O.228.228;3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237;3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166;3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244;3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236;3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157;3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240;3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231;3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154;3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175;3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230;3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239;3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172;3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229;3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238;3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169;3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228;3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237;3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166;3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244;3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236;3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157;3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240;3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231;3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154;3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175;3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230;3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239;3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172;3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229;3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238;3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228;3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237;3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166;3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244;3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236;3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240;3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231;3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.O.172.154;3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175;3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230;3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239;3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172;3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229;3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238;3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169;3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228;3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166;3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;Prodrugs of 3.P 3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231;3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154;3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175;3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230;3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172;3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229;3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238;3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169;3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228;3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166;3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244;3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236;3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157;3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240;3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154;3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175;3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230;3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239;3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172;3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238;3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169;3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228;3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237;3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244;3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236;3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157;3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240;3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231;3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175;3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230;3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239;3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172;3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229;3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169;3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228;3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237;3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166;3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244;3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157;3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240;3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231;3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154;3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175;3.P.244.240; 3.P.244.244; Prodrugs of 3.U 3.U.228.228; 3.U.228.229;3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238;3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228;3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237;3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166;3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244;3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236;3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240;3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231;3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154;3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175;3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230;3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172;3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229;3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238;3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169;3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228;3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166;3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244;3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236;3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157;3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240;3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154;3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175;3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230;3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239;3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172;3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238;3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169;3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228;3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237;3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166;3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236;3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157;3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240;3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231;3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154;3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230;3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239;3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172;3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229;3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238;3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244; Prodrugs of 3.W3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236;3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157;3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240;3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231;3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154;3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230;3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239;3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172;3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229;3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238;3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228;3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237;3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166;3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244;3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236;3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240;3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231;3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154;3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175;3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230;3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172;3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229;3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238;3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169;3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228;3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166;3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244;3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236;3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157;3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240;3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154;3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175;3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230;3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239;3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172;3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238;3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169;3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228;3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237;3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166;3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236;3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157;3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240;3.W.244.244; Prodrugs of 3.Y 3.Y.228.228; 3.Y.228.229; 3.Y.228.230;3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239;3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172;3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238;3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169;3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228;3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237;3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166;3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236;3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157;3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240;3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231;3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154;3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230;3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239;3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172;3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229;3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238;3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169;3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228;3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237;3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166;3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244;3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157;3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240;3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231;3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154;3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175;3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239;3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172;3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229;3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238;3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169;3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237;3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166;3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244;3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236;3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157;3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231;3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154;3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175;3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230;3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239;3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244; Prodrugs of 4.B 4.B.228.228;4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166;4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244;4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236;4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157;4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240;4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154;4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175;4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230;4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239;4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172;4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238;4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169;4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228;4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237;4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166;4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236;4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157;4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240;4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231;4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154;4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230;4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239;4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172;4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229;4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238;4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228;4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237;4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166;4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244;4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157;4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240;4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231;4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154;4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175;4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239;4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172;4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229;4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238;4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169;4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237;4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166;4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;Prodrugs of 4.D 4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231;4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154;4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175;4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230;4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172;4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229;4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238;4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169;4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228;4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166;4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244;4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236;4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157;4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240;4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154;4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175;4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230;4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239;4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172;4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238;4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169;4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228;4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237;4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166;4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236;4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157;4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240;4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231;4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154;4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230;4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239;4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172;4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229;4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238;4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228;4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237;4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166;4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244;4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236;4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240;4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231;4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154;4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175;4.D.244.240; 4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229;4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169;4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228;4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237;4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244;4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157;4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240;4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231;4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154;4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175;4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239;4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172;4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229;4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238;4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169;4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237;4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166;4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244;4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236;4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157;4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231;4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154;4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175;4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230;4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239;4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229;4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238;4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169;4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228;4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237;4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244;4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236;4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157;4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240;4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231;4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175;4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230;4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239;4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172;4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229;4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169;4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236;4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157;4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240;4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231;4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154;4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230;4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239;4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172;4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229;4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238;4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228;4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237;4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166;4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244;4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236;4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240;4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231;4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154;4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175;4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230;4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172;4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229;4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238;4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169;4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228;4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166;4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244;4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236;4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157;4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231;4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154;4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175;4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230;4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239;4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229;4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238;4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169;4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228;4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237;4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244;4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236;4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157;4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240;4.G.244.244; Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230;4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239;4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172;4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238;4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169;4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228;4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237;4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166;4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236;4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157;4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240;4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231;4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154;4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230;4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239;4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172;4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229;4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238;4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228;4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237;4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166;4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244;4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236;4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240;4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231;4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154;4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175;4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230;4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172;4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229;4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238;4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169;4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228;4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166;4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244;4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236;4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157;4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240;4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154;4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175;4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230;4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239;4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172;4.I.244.175; 4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228;4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166;4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244;4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236;4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157;4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240;4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154;4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175;4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230;4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239;4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172;4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238;4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169;4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228;4.J.237.229; 4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237;4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166;4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236;4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157;4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240;4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231;4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154;4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230;4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239;4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172;4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229;4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238;4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228;4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237;4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166;4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244;4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236;4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240;4.J.169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231;4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154;4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175;4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230;4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172;4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229;4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238;4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169;4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228;4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166;4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;Prodrugs of 4.L 4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231;4.L.228.236; 4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154;4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175;4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230;4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172;4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229;4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238;4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169;4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228;4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166;4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244;4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236;4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157;4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240;4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154;4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175;4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230;4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239;4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172;4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238;4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169;4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228;4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237;4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236;4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157;4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240;4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231;4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175;4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230;4.L.169.231; 4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239;4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172;4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229;4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169;4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228;4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237;4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166;4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244;4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157;4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240;4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231;4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154;4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175;4.L.244.240; 4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229;4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238;4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169;4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228;4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237;4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166;4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244;4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236;4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157;4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240;4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231;4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154;4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175;4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230;4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239;4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172;4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229;4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238;4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169;4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228;4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237;4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166;4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244;4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236;4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157;4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240;4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231;4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154;4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175;4.O.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230;4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239;4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172;4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229;4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238;4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169;4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228;4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237;4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244;4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236;4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157;4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240;4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231;4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175;4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230;4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239;4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172;4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229;4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169;4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236;4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157;4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240;4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231;4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154;4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230;4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239;4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172;4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229;4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238;4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228;4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237;4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166;4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244;4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236;4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240;4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231;4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154;4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175;4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230;4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172;4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229;4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238;4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169;4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228;4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166;4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244;4.P.166.228; 4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236;4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157;4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240;4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154;4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175;4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230;4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239;4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172;4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238;4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169;4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228;4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237;4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166;4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236;4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157;4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240;4.P.244.244; Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230;4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239;4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172;4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238;4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169;4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228;4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237;4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166;4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236;4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157;4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240;4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231;4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154;4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230;4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239;4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172;4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229;4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238;4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228;4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237;4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166;4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244;4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236;4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240;4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231;4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154;4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175;4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230;4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172;4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229;4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238;4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169;4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237;4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166;4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244;4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236;4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157;4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231;4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154;4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175;4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230;4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239;4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228;4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166;4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244;4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236;4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157;4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240;4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154;4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175;4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230;4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239;4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172;4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238;4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169;4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228;4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237;4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166;4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236;4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157;4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240;4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231;4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154;4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230;4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239;4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172;4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229;4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228;4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237;4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166;4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244;4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236;4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240;4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231;4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154;4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175;4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230;4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172;4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229;4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238;4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169;4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228;4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166;4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;Prodrugs of 4.Y 4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231;4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154;4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175;4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239;4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172;4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229;4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238;4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169;4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237;4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166;4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244;4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236;4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231;4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154;4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175;4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230;4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239;4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229;4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238;4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169;4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228;4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237;4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244;4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236;4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157;4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240;4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231;4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175;4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230;4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239;4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172;4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229;4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169;4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228;4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237;4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166;4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244;4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157;4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240;4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231;4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154;4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175;4.Y.244.240; 4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229;5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238;5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228;5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237;5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166;5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244;5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236;5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240;5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231;5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154;5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175;5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230;5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172;5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229;5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238;5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169;5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228;5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166;5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244;5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236;5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157;5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240;5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154;5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175;5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230;5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239;5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229;5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238;5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169;5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228;5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237;5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244;5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236;5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157;5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240;5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231;5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175;5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230;5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239;5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172;5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238;5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169;5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236;5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157;5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240;5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231;5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154;5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230;5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239;5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172;5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229;5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238;5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228;5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237;5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166;5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244;5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236;5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240;5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231;5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154;5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175;5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230;5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172;5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229;5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238;5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169;5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228;5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166;5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244;5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236;5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157;5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240;5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154;5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175;5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230;5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239;5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172;5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238;5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169;5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228;5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237;5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166;5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236;5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157;5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240;5.D.244.244; Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230;5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239;5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172;5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238;5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169;5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228;5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237;5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166;5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236;5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157;5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240;5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231;5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154;5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230;5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239;5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172;5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229;5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238;5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228;5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237;5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166;5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244;5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236;5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240;5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231;5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154;5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175;5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230;5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172;5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229;5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238;5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169;5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228;5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166;5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244;5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236;5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157;5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240;5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154;5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175;5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230;5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239;5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172;5.E.244.175; 5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228;5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166;5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244;5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236;5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157;5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240;5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154;5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175;5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230;5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239;5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172;5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238;5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169;5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228;5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237;5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166;5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236;5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157;5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240;5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231;5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154;5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230;5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239;5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172;5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229;5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169;5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228;5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237;5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166;5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244;5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157;5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240;5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231;5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154;5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175;5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239;5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172;5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229;5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238;5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169;5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237;5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166;5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;Prodrugs of 5.I 5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154;5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175;5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230;5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172;5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229;5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238;5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169;5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228;5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166;5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244;5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236;5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157;5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240;5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154;5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175;5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230;5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239;5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172;5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238;5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169;5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228;5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237;5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166;5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236;5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157;5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240;5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231;5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154;5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230;5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239;5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172;5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229;5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238;5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228;5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237;5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166;5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244;5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236;5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240;5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231;5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154;5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175;5.I.244.240; 5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229;5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238;5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228;5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237;5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166;5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244;5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236;5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240;5.J.230.244; 5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231;5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154;5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175;5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230;5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172;5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229;5.J.237.230; 5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238;5.J.237.239; 5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169;5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228;5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166;5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244;5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236;5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157;5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240;5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154;5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175;5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230;5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239;5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172;5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238;5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169;5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228;5.J.169.229; 5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237;5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166;5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236;5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157;5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240;5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231;5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154;5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230;5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239;5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172;5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229;5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238;5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236;5.L.228.237; 5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157;5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240;5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231;5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154;5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230;5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239;5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172;5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229;5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238;5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228;5.L.236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237;5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166;5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244;5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236;5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240;5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231;5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154;5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175;5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239;5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172;5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229;5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238;5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169;5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237;5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166;5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244;5.L.166.228; 5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236;5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157;5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231;5.L.169.236; 5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154;5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175;5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230;5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239;5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229;5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238;5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169;5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228;5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237;5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244;5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236;5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157;5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240;5.L.244.244; Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230;5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239;5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172;5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229;5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238;5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169;5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228;5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237;5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166;5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244;5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236;5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157;5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240;5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231;5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154;5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175;5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230;5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239;5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172;5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229;5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238;5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169;5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228;5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237;5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166;5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244;5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236;5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157;5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240;5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231;5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154;5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175;5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230;5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172;5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229;5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238;5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169;5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166;5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244;5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236;5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157;5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231;5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154;5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175;5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230;5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239;5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228;5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166;5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244;5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236;5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157;5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240;5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154;5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175;5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230;5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239;5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172;5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238;5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169;5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228;5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237;5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166;5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236;5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157;5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240;5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231;5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154;5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230;5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239;5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172;5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229;5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238;5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228;5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237;5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166;5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244;5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236;5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240;5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231;5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154;5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175;5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230;5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172;5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229;5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238;5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169;5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228;5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166;5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231;5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154;5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175;5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239;5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172;5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229;5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238;5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169;5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237;5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166;5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244;5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236;5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157;5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231;5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154;5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175;5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230;5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239;5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229;5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238;5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169;5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228;5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237;5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244;5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236;5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157;5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240;5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231;5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175;5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230;5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239;5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172;5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229;5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169;5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228;5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237;5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166;5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244;5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157;5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240;5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231;5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154;5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175;5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228; 5.W.228.229;5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169;5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228;5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237;5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166;5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244;5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157;5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240;5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231;5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154;5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175;5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239;5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172;5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229;5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238;5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169;5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228;5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237;5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166;5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244;5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236;5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240;5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231;5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154;5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175;5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230;5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172;5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229;5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238;5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169;5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228;5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166;5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244;5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236;5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157;5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240;5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154;5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175;5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230;5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239;5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172;5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238;5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169;5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244; Prodrugs of 5.Y5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236;5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157;5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240;5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231;5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154;5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230;5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239;5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172;5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229;5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238;5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228;5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237;5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166;5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244;5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236;5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240;5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231;5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154;5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175;5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230;5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172;5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229;5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238;5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169;5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228;5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166;5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244;5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236;5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157;5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240;5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154;5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175;5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230;5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239;5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229;5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238;5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169;5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228;5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237;5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244;5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236;5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157;5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240;5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229; 6.B.228.230;6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239;6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172;6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238;6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169;6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228;6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237;6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166;6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236;6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157;6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240;6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231;6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154;6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230;6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239;6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172;6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229;6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238;6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228;6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237;6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166;6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244;6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236;6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240;6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231;6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154;6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175;6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230;6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172;6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229;6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238;6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169;6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228;6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237;6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166;6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244;6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236;6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157;6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240;6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231;6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154;6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175;6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230;6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239;6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172;6.B.244.175; 6.B.244.240; 6.B.244.244; Prodrugs of 6.D 6.D.228.228;6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237;6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166;6.D.228.169; 6.D.228.172; 6.D.228.175; 6.D.228.240; 6.D.228.244;6.D.229.228; 6.D.229.229; 6.D.229.230; 6.D.229.231; 6.D.229.236;6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154; 6.D.229.157;6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175; 6.D.229.240;6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230; 6.D.230.231;6.D.230.236; 6.D.230.237; 6.D.230.238; 6.D.230.239; 6.D.230.154;6.D.230.157; 6.D.230.166; 6.D.230.169; 6.D.230.172; 6.D.230.175;6.D.230.240; 6.D.230.244; 6.D.231.228; 6.D.231.229; 6.D.231.230;6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238; 6.D.231.239;6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169; 6.D.231.172;6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228; 6.D.236.229;6.D.236.230; 6.D.236.231; 6.D.236.236; 6.D.236.237; 6.D.236.238;6.D.236.239; 6.D.236.154; 6.D.236.157; 6.D.236.166; 6.D.236.169;6.D.236.172; 6.D.236.175; 6.D.236.240; 6.D.236.244; 6.D.237.228;6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236; 6.D.237.237;6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157; 6.D.237.166;6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240; 6.D.237.244;6.D.238.228; 6.D.238.229; 6.D.238.230; 6.D.238.231; 6.D.238.236;6.D.238.237; 6.D.238.238; 6.D.238.239; 6.D.238.154; 6.D.238.157;6.D.238.166; 6.D.238.169; 6.D.238.172; 6.D.238.175; 6.D.238.240;6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230; 6.D.239.231;6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239; 6.D.239.154;6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172; 6.D.239.175;6.D.239.240; 6.D.239.244; 6.D.154.228; 6.D.154.229; 6.D.154.230;6.D.154.231; 6.D.154.236; 6.D.154.237; 6.D.154.238; 6.D.154.239;6.D.154.154; 6.D.154.157; 6.D.154.166; 6.D.154.169; 6.D.154.172;6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228; 6.D.157.229;6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237; 6.D.157.238;6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166; 6.D.157.169;6.D.157.172; 6.D.157.175; 6.D.157.240; 6.D.157.244; 6.D.166.228;6.D.166.229; 6.D.166.230; 6.D.166.231; 6.D.166.236; 6.D.166.237;6.D.166.238; 6.D.166.239; 6.D.166.154; 6.D.166.157; 6.D.166.166;6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240; 6.D.166.244;6.D.169.228; 6.D.169.229; 6.D.169.230; 6.D.169.231; 6.D.169.236;6.D.169.237; 6.D.169.238; 6.D.169.239; 6.D.169.154; 6.D.169.157;6.D.169.166; 6.D.169.169; 6.D.169.172; 6.D.169.175; 6.D.169.240;6.D.169.244; 6.D.172.228; 6.D.172.229; 6.D.172.230; 6.D.172.231;6.D.172.236; 6.D.172.237; 6.D.172.238; 6.D.172.239; 6.D.172.154;6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172; 6.D.172.175;6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D.175.229; 6.D.175.230;6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238; 6.D.175.239;6.D.175.154; 6.D.175.157; 6.D.175.166; 6.D.175.169; 6.D.175.172;6.D.175.175; 6.D.175.240; 6.D.175.244; 6.D.240.228; 6.D.240.229;6.D.240.230; 6.D.240.231; 6.D.240.236; 6.D.240.237; 6.D.240.238;6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166; 6.D.240.169;6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244; 6.D.244.228;6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236; 6.D.244.237;6.D.244.238; 6.D.244.239; 6.D.244.154; 6.D.244.157; 6.D.244.166;6.D.244.169; 6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231;6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154;6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175;6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230;6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172;6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229;6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238;6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169;6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228;6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166;6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244;6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236;6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157;6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240;6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231;6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154;6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175;6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230;6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239;6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172;6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229;6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238;6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169;6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228;6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237;6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166;6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244;6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236;6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157;6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240;6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231;6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154;6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175;6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230;6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239;6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172;6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E.172.229;6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238;6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169;6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228;6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237;6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166;6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244;6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236;6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157;6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240;6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231;6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154;6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175;6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228; 6.G.228.229;6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238;6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228;6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237;6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166;6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244;6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236;6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240;6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231;6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154;6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175;6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229; 6.G.236.230;6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239;6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172;6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229;6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237; 6.G.237.238;6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166; 6.G.237.169;6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228;6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237;6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166;6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244;6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236;6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157;6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240;6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231;6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154;6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175;6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230;6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239;6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172;6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238;6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169;6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228;6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237;6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166;6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236;6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157;6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240;6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231;6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154;6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230;6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239;6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172;6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229;6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238;6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244; Prodrugs of 6.I6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236;6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157;6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240;6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231;6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154;6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230;6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239;6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172;6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229;6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238;6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228;6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237;6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166;6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244;6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236;6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240;6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231;6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154;6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175;6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230;6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172;6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229;6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238;6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169;6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228;6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166;6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244;6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236;6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157;6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240;6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154;6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175;6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230;6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239;6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172;6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238;6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169;6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228;6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237;6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166;6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236;6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157;6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240;6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229; 6.J.228.230;6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238; 6.J.228.239;6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169; 6.J.228.172;6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238;6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169;6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J.230.228;6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237;6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157; 6.J.230.166;6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236;6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157;6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240;6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230; 6.J.236.231;6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154;6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230;6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239;6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169; 6.J.237.172;6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228; 6.J.238.229;6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238;6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228;6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237;6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166;6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244;6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236;6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240;6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231;6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154;6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175;6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229; 6.J.166.230;6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172;6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229;6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237; 6.J.169.238;6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166; 6.J.169.169;6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237;6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166;6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244;6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236;6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157;6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231;6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154;6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175;6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230;6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239;6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L 6.L.228.228;6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166;6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244;6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236;6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157;6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240;6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154;6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175;6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230;6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239;6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172;6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238;6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169;6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228;6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237;6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166;6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236;6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157;6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240;6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231;6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154;6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230;6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239;6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172;6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229;6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238;6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228;6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237;6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166;6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244;6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240;6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231;6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154;6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175;6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230;6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172;6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229;6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238;6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169;6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228;6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166;6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231;6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154;6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175;6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230;6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239;6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172;6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229;6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238;6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169;6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228;6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237;6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166;6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244;6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236;6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157;6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240;6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231;6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154;6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175;6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230;6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239;6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172;6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229;6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238;6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169;6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228;6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237;6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166;6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244;6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236;6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157;6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240;6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231;6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175;6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230;6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239;6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172;6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229;6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169;6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228;6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237;6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166;6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244;6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157;6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240;6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231;6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154;6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175;6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228; 6.P.228.229;6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238;6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228;6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237;6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166;6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244;6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236;6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157;6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240;6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231;6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154;6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175;6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230;6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239;6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172;6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229;6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238;6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169;6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228;6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237;6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166;6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244;6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236;6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157;6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240;6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231;6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154;6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175;6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229; 6.P.157.230;6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239;6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172;6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229;6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238;6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169;6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P.169.228;6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236; 6.P.169.237;6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166;6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244;6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236;6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157;6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240;6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231;6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175;6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230;6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239;6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229;6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169;6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244; Prodrugs of 6.U6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236;6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157;6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240;6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231;6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154;6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175;6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230;6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239;6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172;6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229;6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238;6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169;6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228;6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237;6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166;6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244;6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236;6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157;6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240;6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231;6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154;6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175;6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230;6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172;6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229;6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238;6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169;6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228;6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166;6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244;6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236;6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157;6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240;6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154;6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175;6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230;6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239;6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172;6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238;6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169;6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228;6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237;6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166;6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236;6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157;6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240;6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229; 6.W.228.230;6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239;6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172;6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238;6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169;6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228;6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237;6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166;6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236;6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157;6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240;6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231;6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154;6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230;6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239;6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172;6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229;6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238;6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228;6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237;6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166;6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244;6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236;6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240;6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231;6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154;6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175;6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230;6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172;6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229;6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238;6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169;6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228;6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166;6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244;6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236;6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157;6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240;6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154;6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175;6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230;6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239;6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172;6.W.244.175; 6.W.244.240; 6.W.244.244; Prodrugs of 6.Y 6.Y.228.228;6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166;6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244;6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236;6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157;6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240;6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154;6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175;6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230;6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239;6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172;6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238;6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169;6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228;6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237;6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166;6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236;6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157;6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240;6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231;6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154;6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230;6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239;6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172;6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229;6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169;6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228;6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237;6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166;6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244;6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157;6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240;6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231;6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154;6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175;6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239;6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172;6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229;6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238;6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169;6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237;6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166;6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;Prodrugs of 7.AH 7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223;7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158;7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244;7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH.15.196;7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247;7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240;7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243;7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223;7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157;7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244;7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196;7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240;7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158;7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243;7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223;7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157;7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244;7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196;7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247; Prodrugs of 7.AJ 7.AJ.4.157; 7.AJ.4.158;7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247;7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244;7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223;7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243; 7.AJ.157.247; 7.AJ.196.157;7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244;7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247;7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240;7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158;7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223;7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247; Prodrugs of 7.AN7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240;7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158;7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243;7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223;7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157;7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196;7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247;7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240;7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158;7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243;7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157;7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244;7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196;7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247;7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240;7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243;7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223;7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157;7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196;7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;Prodrugs of 7.AP 7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223;7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158;7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244;7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196;7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247;7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240;7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243;7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223;7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157;7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244;7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196;7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240;7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158;7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243;7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223;7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157;7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244;7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196;7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240;7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158;7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243;7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247; Prodrugs of 7.AZ 7.AZ.4.157; 7.AZ.4.158;7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247;7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244;7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223;7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157;7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244;7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247;7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240;7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158;7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223;7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247; Prodrugs of 7.BF7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240;7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158;7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244; 7.BF.16.243;7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223;7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244;7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196;7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247;7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240;7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158;7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223;7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157;7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244;7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196;7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247;7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240;7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243;7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223;7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157;7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196;7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;Prodrugs of 7.CI 7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223;7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158;7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244;7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196;7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247;7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240;7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243;7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223;7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157;7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244;7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196;7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240;7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158;7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243;7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223;7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157;7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244;7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247;7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240;7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158;7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223;7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157;7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158;7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244;7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223;7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157;7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196;7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247;7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240;7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158;7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243;7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157;7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244;7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247;7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240;7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243;7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223;7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157;7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196;7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247;7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240;7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243;7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223;7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; Prodrugs of 8.AH8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247;8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240;8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158;8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223;8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157;8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244;8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223;8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158;8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247;8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244;8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196;8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247;8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158;8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243;8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223;8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157;8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244;8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247;8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240;8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158;8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243;8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223;8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157; 8.AN.4.158;8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247;8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244;8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223;8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157;8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196;8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247;8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240;8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158;8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243;8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157;8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244;8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196;8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247;8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240;8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243;8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157;8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244;8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196;8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240;8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158;8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243;8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of 8.AP8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240;8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158;8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243;8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223;8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157;8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196;8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247;8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240;8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158;8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243;8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157;8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244;8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247;8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240;8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158;8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223;8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157;8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244;8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223;8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158;8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247;8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244;8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196;8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247;8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158;8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243;8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223;8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157;8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244;8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247;8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240;8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158;8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243;8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223;8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196;8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247;8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240;8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243;8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223;8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157;8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157; 8.BF.4.158;8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247;8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223;8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157;8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196;8.BF.16.223; 8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247;8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240;8.BF.18.244; 8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158;8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223;8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157;8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244;8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196;8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247;8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158;8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243;8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247; 8.BF.196.157;8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244;8.BF.196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196;8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240;8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158;8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243;8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of 8.CI8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240;8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158;8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243;8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223;8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157;8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196;8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247;8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240;8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158;8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243;8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223;8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157;8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244;8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247;8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240;8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158;8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223;8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157;8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244;8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223;8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158;8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247;8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244;8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196;8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247;8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240;8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243;8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223;8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157;8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244;8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196;8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240;8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158;8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243;8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223;8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157;8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196;8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247;8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240;8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243;8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223;8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157;8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157; 9.AH.4.158;9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247;9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244;9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223;9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157;9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244;9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196;9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247;9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240;9.AH.18.244; 9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158;9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243;9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223;9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157;9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244;9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196;9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247;9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240;9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158;9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243;9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247; 9.AH.196.157;9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244;9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196;9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240;9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158;9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of 9.AJ9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240;9.AJ.15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158;9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243;9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223;9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157;9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196;9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247;9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240;9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158;9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243;9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157;9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244;9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247;9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240;9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158;9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223;9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157;9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244;9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223;9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158;9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247;9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244;9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196;9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247;9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240;9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243;9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223;9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157;9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244;9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196;9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240;9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158;9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243;9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223;9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157;9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196;9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247;9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240;9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243;9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223;9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157;9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157; 9.AP.4.158;9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247;9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244;9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223;9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157;9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244;9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196;9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247;9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240;9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158;9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243;9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223;9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157;9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244;9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196;9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247;9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240;9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158;9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243;9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157;9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244;9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196;9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240;9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158;9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243;9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of 9.AZ9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247;9.AZ.15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240;9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158;9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243;9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223;9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244;9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196;9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247;9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240;9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158;9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223;9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157;9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244;9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247;9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223; 9.AZ.196.240;9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158;9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223;9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157;9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244;9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223;9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158;9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247;9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244;9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196;9.BF.15.223; 9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247;9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240;9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243;9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223;9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157;9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244;9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247;9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240;9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158;9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243;9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223;9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247;9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240;9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243;9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223;9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157;9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157; 9.CI.4.158;9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247;9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244;9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223;9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157;9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244;9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196;9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247;9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240;9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158;9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243;9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223;9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157;9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244;9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196;9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247;9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240;9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158;9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243;9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157;9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244;9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196;9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240;9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158;9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243;9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of 9.CO9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240;9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158;9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223;9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157;9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244;9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196;9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247;9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240;9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158;9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223;9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157;9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244;9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247;9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240;9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158;9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223;9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157;9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244;9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223;10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157;10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244;10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196;10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247;10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240;10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158;10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223;10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157;10.AH.56.158; 10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244;10.AH.56.243; 10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196;10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247;10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240;10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157; 10.AJ.7.158;10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243;10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223;10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157;10.AJ.16.158; 10.AJ.16.196; 10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244;10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243; 10.AJ.18.247;10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240;10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158;10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223;10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157;10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244;10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247;10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; 10.AJ.56.240;10.AJ.56.244; 10.AJ.56.243; 10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158;10.AJ.157.196; 10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244;10.AJ.157.243; 10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158;10.AJ.196.196; 10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244;10.AJ.196.243; 10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158;10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244;10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158;10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244;10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158;10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244;10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158;10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244;10.AJ.247.243; 10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157;10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196;10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247;10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240;10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158;10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223;10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157;10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244;10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247;10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240;10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158;10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223;10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157;10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244;10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247;10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247;10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223;10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247;10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223;10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223;10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247;10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223;10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247;10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247; Prodrugs of10.AP 10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240;10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158;10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243;10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223;10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157;10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244;10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247;10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240;10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158;10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223;10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157;10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244;10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247;10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240;10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158;10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196;10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247;10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240;10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243;10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223;10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157;10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244;10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247;10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240;10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158;10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223;10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157;10.AZ.54.158; 10.AZ.54.196; 10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244;10.AZ.54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247;10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240;10.AZ.56.244; 10.AZ.56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158;10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244;10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158;10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158;10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244;10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158;10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244;10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244;10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158;10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244;10.AZ.247.243; 10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157;10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244;10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196;10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247;10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240;10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158;10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223;10.BF.16.240; 10.BF.16.244; 10.BF.16.243; 10.BF.16.247; 10.BF.18.157;10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244;10.BF.18.243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247;10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240;10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158;10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BF.54.223;10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157;10.BF.55.158; 10.BF.55.196; 10.BF.55.223; 10.BF.55.240; 10.BF.55.244;10.BF.55.243; 10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247;10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF.157.223;10.BF.157.240; 10.BF.157.244; 10.BF.157.243; 10.BF.157.247;10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF.196.223;10.BF.196.240; 10.BF.196.244; 10.BF.196.243; 10.BF.196.247;10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223;10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247;10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223;10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247;10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223;10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247;10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223;10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247; Prodrugs of10.CI 10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240;10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244;10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196;10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247;10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158;10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158;10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243;10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196;10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243;10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196;10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196;10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243;10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196;10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243;10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243;10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196;10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243;10.CI.247.247; Prodrugs of 10.CO 10.CO.4.157; 10.CO.4.158; 10.CO.4.196;10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247;10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240;10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243;10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223;10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244;10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196;10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158;10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243;10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223;10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244;10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196;10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247;10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158;10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244;10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158;10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244;10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244;10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158;10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244;10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158;10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158;10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244;10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH 11.AH.4.157;11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196;11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247;11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240;11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158;11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11.AH.15.244; 11.AH.15.243;11.AH.15.247; 11.AH.16.157; 11.AH.16.158; 11.AH.16.196; 11.AH.16.223;11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244;11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196;11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11.AH.26.243; 11.AH.26.247;11.AH.27.157; 11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158;11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243;11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196; 11.AH.54.223;11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244;11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH.56.196;11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11.AH.56.247;11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247;11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223;11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247;11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223;11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223;11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247;11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223;11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247;11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of11.AJ 11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240; 11.AJ.15.244;11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158; 11.AJ.16.196;11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247;11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157; 11.AJ.26.158;11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244; 11.AJ.26.243;11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223;11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244;11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158; 11.AJ.54.196;11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247;11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158;11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243;11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243;11.AJ.157.247; 11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196;11.AJ.196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243;11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196;11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196;11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243;11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196;11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243;11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243;11.AJ.247.247; Prodrugs of 11.AN 11.AN.4.157; 11.AN.4.158; 11.AN.4.196;11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247;11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240;11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158;11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243;11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223;11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244;11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196;11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247;11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158;11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243;11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223;11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244;11.AN.54.243; 11.AN.54.247; 11.AN.55.157; 11.AN.55.158; 11.AN.55.196;11.AN.55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247;11.AN.56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158;11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244;11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158;11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244;11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158;11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244;11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158;11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244;11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158;11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244;11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158;11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244;11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP 11.AP.4.157;11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196;11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247;11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240;11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158;11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243;11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP.16.196; 11.AP.16.223;11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244;11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196;11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247;11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158;11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243;11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223;11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244;11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196;11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247;11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223;11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223;11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247;11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223;11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247;11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247;11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223;11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247;11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223;11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of11.AZ 11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240; 11.AZ.15.244;11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158; 11.AZ.16.196;11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247;11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157; 11.AZ.26.158;11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244; 11.AZ.26.243;11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223;11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240; 11.AZ.29.244;11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158; 11.AZ.54.196;11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247;11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157; 11.AZ.56.158;11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244; 11.AZ.56.243;11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243;11.AZ.157.247; 11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196;11.AZ.196.223; 11.AZ.196.240; 11.AZ.196.244; 11.AZ.196.243;11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196;11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196;11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243;11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196;11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243;11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243;11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157; 11.BF.4.158; 11.BF.4.196;11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247;11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240;11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243;11.BF.7.247; 11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223;11.BF.15.240; 11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157;11.BF.16.158; 11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196;11.BF.18.223; 11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247;11.BF.26.157; 11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240;11.BF.26.244; 11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243;11.BF.27.247; 11.BF.29.157; 11.BF.29.158; 11.BF.29.196; 11.BF.29.223;11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF.54.157;11.BF.54.158; 11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11.BF.55.196;11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247;11.BF.56.157; 11.BF.56.158; 11.BF.56.196; 11.BF.56.223; 11.BF.56.240;11.BF.56.244; 11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243;11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223;11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157;11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196;11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247;11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240;11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243;11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223;11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157;11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196;11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247;11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247;11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223;11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247;11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223;11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223;11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247;11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223;11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247;11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247; Prodrugs of11.CO 11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240;11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158;11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243;11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223;11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247;11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240;11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243;11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196;11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243;11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196;11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196;11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243;11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196;11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243;11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243;11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196;11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243;11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157; 12.AH.4.158; 12.AH.4.196;12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AH.4.243; 12.AH.4.247;12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240;12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158;12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243;12.AH.7.247; 12.AH.15.157; 12.AH.15.158; 12.AH.15.196; 12.AH.15.223;12.AH.15.240; 12.AH.15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157;12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196;12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247;12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240;12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243;12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223;12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157;12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196;12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247;12.AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240;12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244; 12.AJ.15.243;12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158; 12.AJ.16.196; 12.AJ.16.223;12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157;12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196;12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247;12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240;12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243;12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223;12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157;12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196;12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247;12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247;12.AJ.196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223;12.AJ.196.240; 12.AJ.196.244; 12.AJ.196.243; 12.AJ.196.247;12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223;12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223;12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247;12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223;12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223;12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247; Prodrugs of12.AN 12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240;12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158;12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243;12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223;12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157;12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196;12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247;12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240;12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243;12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223;12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157;12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196;12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247;12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240;12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243;12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243;12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196;12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243;12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196;12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196;12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243;12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196;12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196;12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243;12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157; 12.AP.4.158; 12.AP.4.196;12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247;12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240;12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243;12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223;12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157;12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196;12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247;12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158;12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243;12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223;12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244;12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196;12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247;12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158;12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244;12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244;12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158;12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244;12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244;12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158;12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244;12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158;12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ 12.AZ.4.157;12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244;12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196;12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247;12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240;12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158;12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243;12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223;12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244;12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196;12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247;12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158;12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243;12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223;12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244;12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196;12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247;12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223;12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247;12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223;12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247;12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223;12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247;12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223;12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247;12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223;12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247;12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223;12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of12.BF 12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244;12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196;12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243; 12.BF.16.247;12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158;12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243;12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223;12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244;12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196;12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247;12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158;12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243;12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243;12.BF.157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196;12.BF.196.223; 12.BF.196.240; 12.BF.196.244; 12.BF.196.243;12.BF.196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196;12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196;12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243;12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196;12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243;12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243;12.BF.247.247; Prodrugs of 12.CI 12.CI.4.157; 12.CI.4.158; 12.CI.4.196;12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247;12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240;12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243;12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223;12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244;12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196;12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247;12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158;12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243;12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223;12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244;12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196;12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247;12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158;12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244;12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158;12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158;12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244;12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158;12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244;12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158;12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244;12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO 12.CO.4.157;12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196;12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247;12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240;12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158;12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243;12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223;12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244;12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196;12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247;12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158;12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243;12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223;12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244;12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196;12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247;12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223;12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223;12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247;12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223;12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247;12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247;12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223;12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247;12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223;12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of13.B 13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154;13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175;13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230;13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172;13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229;13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238;13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228;13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237;13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166;13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236;13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157;13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240;13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231;13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154;13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175;13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230;13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239;13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172;13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229;13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238;13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169;13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228;13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237;13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166;13.B.154.169; 13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244;13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236;13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157;13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240;13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154;13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175;13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230;13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172;13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229;13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238;13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228;13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237;13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166;13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236;13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157;13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240;13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154;13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175;13.B.244.240; 13.B.244.244; Prodrugs of 13.D 13.D.228.228; 13.D.228.229;13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238;13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228;13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237;13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166;13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;13.D.230.228; 13.D.230.229; 13.D.230.230; 13.D.230.231; 13.D.230.236;13.D.230.237; 13.D.230.238; 13.D.230.239; 13.D.230.154; 13.D.230.157;13.D.230.166; 13.D.230.169; 13.D.230.172; 13.D.230.175; 13.D.230.240;13.D.230.244; 13.D.231.228; 13.D.231.229; 13.D.231.230; 13.D.231.231;13.D.231.236; 13.D.231.237; 13.D.231.238; 13.D.231.239; 13.D.231.154;13.D.231.157; 13.D.231.166; 13.D.231.169; 13.D.231.172; 13.D.231.175;13.D.231.240; 13.D.231.244; 13.D.236.228; 13.D.236.229; 13.D.236.230;13.D.236.231; 13.D.236.236; 13.D.236.237; 13.D.236.238; 13.D.236.239;13.D.236.154; 13.D.236.157; 13.D.236.166; 13.D.236.169; 13.D.236.172;13.D.236.175; 13.D.236.240; 13.D.236.244; 13.D.237.228; 13.D.237.229;13.D.237.230; 13.D.237.231; 13.D.237.236; 13.D.237.237; 13.D.237.238;13.D.237.239; 13.D.237.154; 13.D.237.157; 13.D.237.166; 13.D.237.169;13.D.237.172; 13.D.237.175; 13.D.237.240; 13.D.237.244; 13.D.238.228;13.D.238.229; 13.D.238.230; 13.D.238.231; 13.D.238.236; 13.D.238.237;13.D.238.238; 13.D.238.239; 13.D.238.154; 13.D.238.157; 13.D.238.166;13.D.238.169; 13.D.238.172; 13.D.238.175; 13.D.238.240; 13.D.238.244;13.D.239.228; 13.D.239.229; 13.D.239.230; 13.D.239.231; 13.D.239.236;13.D.239.237; 13.D.239.238; 13.D.239.239; 13.D.239.154; 13.D.239.157;13.D.239.166; 13.D.239.169; 13.D.239.172; 13.D.239.175; 13.D.239.240;13.D.239.244; 13.D.154.228; 13.D.154.229; 13.D.154.230; 13.D.154.231;13.D.154.236; 13.D.154.237; 13.D.154.238; 13.D.154.239; 13.D.154.154;13.D.154.157; 13.D.154.166; 13.D.154.169; 13.D.154.172; 13.D.154.175;13.D.154.240; 13.D.154.244; 13.D.157.228; 13.D.157.229; 13.D.157.230;13.D.157.231; 13.D.157.236; 13.D.157.237; 13.D.157.238; 13.D.157.239;13.D.157.154; 13.D.157.157; 13.D.157.166; 13.D.157.169; 13.D.157.172;13.D.157.175; 13.D.157.240; 13.D.157.244; 13.D.166.228; 13.D.166.229;13.D.166.230; 13.D.166.231; 13.D.166.236; 13.D.166.237; 13.D.166.238;13.D.166.239; 13.D.166.154; 13.D.166.157; 13.D.166.166; 13.D.166.169;13.D.166.172; 13.D.166.175; 13.D.166.240; 13.D.166.244; 13.D.169.228;13.D.169.229; 13.D.169.230; 13.D.169.231; 13.D.169.236; 13.D.169.237;13.D.169.238; 13.D.169.239; 13.D.169.154; 13.D.169.157; 13.D.169.166;13.D.169.169; 13.D.169.172; 13.D.169.175; 13.D.169.240; 13.D.169.244;13.D.172.228; 13.D.172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236;13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154; 13.D.172.157;13.D.172.166; 13.D.172.169; 13.D.172.172; 13.D.172.175; 13.D.172.240;13.D.172.244; 13.D.175.228; 13.D.175.229; 13.D.175.230; 13.D.175.231;13.D.175.236; 13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154;13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172; 13.D.175.175;13.D.175.240; 13.D.175.244; 13.D.240.228; 13.D.240.229; 13.D.240.230;13.D.240.231; 13.D.240.236; 13.D.240.237; 13.D.240.238; 13.D.240.239;13.D.240.154; 13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172;13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228; 13.D.244.229;13.D.244.230; 13.D.244.231; 13.D.244.236; 13.D.244.237; 13.D.244.238;13.D.244.239; 13.D.244.154; 13.D.244.157; 13.D.244.166; 13.D.244.169;13.D.244.172; 13.D.244.175; 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13.L.175.154;13.L.175.157; 13.L.175.166; 13.L.175.169; 13.L.175.172; 13.L.175.175;13.L.175.240; 13.L.175.244; 13.L.240.228; 13.L.240.229; 13.L.240.230;13.L.240.231; 13.L.240.236; 13.L.240.237; 13.L.240.238; 13.L.240.239;13.L.240.154; 13.L.240.157; 13.L.240.166; 13.L.240.169; 13.L.240.172;13.L.240.175; 13.L.240.240; 13.L.240.244; 13.L.244.228; 13.L.244.229;13.L.244.230; 13.L.244.231; 13.L.244.236; 13.L.244.237; 13.L.244.238;13.L.244.239; 13.L.244.154; 13.L.244.157; 13.L.244.166; 13.L.244.169;13.L.244.172; 13.L.244.175; 13.L.244.240; 13.L.244.244; Prodrugs of 13.O13.O.228.228; 13.O.228.229; 13.O.228.230; 13.O.228.231; 13.O.228.236;13.O.228.237; 13.O.228.238; 13.O.228.239; 13.O.228.154; 13.O.228.157;13.O.228.166; 13.O.228.169; 13.O.228.172; 13.O.228.175; 13.O.228.240;13.O.228.244; 13.O.229.228; 13.O.229.229; 13.O.229.230; 13.O.229.231;13.O.229.236; 13.O.229.237; 13.O.229.238; 13.O.229.239; 13.O.229.154;13.O.229.157; 13.O.229.166; 13.O.229.169; 13.O.229.172; 13.O.229.175;13.O.229.240; 13.O.229.244; 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13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;Prodrugs of 13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154;13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175;13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230;13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172;13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229;13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238;13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228;13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237;13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166;13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 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13.W.154.175; 13.W.154.240; 13.W.154.244;13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236;13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157;13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240;13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154;13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175;13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230;13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172;13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229;13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238;13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228;13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166;13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244;13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236;13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240;13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231;13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154;13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228; 13.Y.228.229;13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238;13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169;13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237;13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166;13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 13.Y.229.244;13.Y.230.228; 13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236;13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154; 13.Y.230.157;13.Y.230.166; 13.Y.230.169; 13.Y.230.172; 13.Y.230.175; 13.Y.230.240;13.Y.230.244; 13.Y.231.228; 13.Y.231.229; 13.Y.231.230; 13.Y.231.231;13.Y.231.236; 13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154;13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172; 13.Y.231.175;13.Y.231.240; 13.Y.231.244; 13.Y.236.228; 13.Y.236.229; 13.Y.236.230;13.Y.236.231; 13.Y.236.236; 13.Y.236.237; 13.Y.236.238; 13.Y.236.239;13.Y.236.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172;13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229;13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238;13.Y.237.239; 13.Y.237.154; 13.Y.237.157; 13.Y.237.166; 13.Y.237.169;13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228;13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237;13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166;13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244;13.Y.239.228; 13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236;13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157;13.Y.239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240;13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231;13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154;13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172; 13.Y.154.175;13.Y.154.240; 13.Y.154.244; 13.Y.157.228; 13.Y.157.229; 13.Y.157.230;13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239;13.Y.157.154; 13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172;13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y.166.229;13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238;13.Y.166.239; 13.Y.166.154; 13.Y.166.157; 13.Y.166.166; 13.Y.166.169;13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228;13.Y.169.229; 13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237;13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166;13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244;13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157;13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240;13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231;13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175;13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230;13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239;13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229;13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238;13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169;13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of14.AH 14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244;14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196;14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247;14.AH.18.157; 14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158;14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243;14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223;14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244;14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196;14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247;14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158;14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243;14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196;14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243;14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196;14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243;14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196;14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243;14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196;14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243;14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196;14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243;14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196;14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243;14.AH.247.247; Prodrugs of 14.AJ 14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196;14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247;14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240;14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243;14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223;14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244;14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196;14.AJ.18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247;14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158;14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243;14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223;14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244;14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196;14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247;14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158;14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244;14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244;14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158;14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244;14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158;14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158;14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244;14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158;14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244;14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN 14.AN.4.157;14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196;14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247;14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240;14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158;14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243;14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223;14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244;14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196;14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247;14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158;14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243;14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223;14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244;14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196;14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247;14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247;14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223;14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247;14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223;14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223;14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247;14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223;14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247;14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of14.AP 14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247;14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158;14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243;14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196;14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243;14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196;14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196;14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243;14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196;14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243;14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243;14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196;14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243;14.AP.247.247; Prodrugs of 14.AZ 14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196;14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247;14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240;14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243;14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223;14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244;14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196;14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247;14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158;14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243;14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223;14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244;14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196;14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247;14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158;14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244;14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158;14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158;14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244;14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158;14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244;14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244;14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158;14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244;14.AZ.247.243; 14.AZ.247.247; Prodrugs of 14.BF 14.BF.4.157;14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196;14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247;14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240;14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158;14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223;14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157;14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244;14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247;14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; 14.BF.27.240;14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158;14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223;14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157;14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244;14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247;14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223;14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223;14.BF.196.240; 14.BF.196.244; 14.BF.196.243; 14.BF.196.247;14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223;14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247;14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247;14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223;14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247;14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223;14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247; Prodrugs of14.CI 14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240;14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158;14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243;14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223;14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157;14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244;14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247;14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240;14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158;14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240;14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158;14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243;14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223;14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157;14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244;14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247;14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240;14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158;14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223;14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157;14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244;14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247;14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240;14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158;14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244;14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158;14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244;14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158;14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244;14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158;14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244;14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158;14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244;14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247.

All literature and patent citations above are hereby expresslyincorporated by reference at the locations of their citation.Specifically cited sections or pages of the above cited works areincorporated by reference with specificity. The invention has beendescribed in detail sufficient to allow one of ordinary skill in the artto make and use the subject matter of the following Claims. It isapparent that certain modifications of the methods and compositions ofthe following Claims can be made within the scope and spirit of theinvention.

In the claims hereinbelow, the subscript and superscripts of a givenvariable are distinct. For example, R₁ is distinct from R¹.

1. A conjugate of the formula:[DRUG]-(A⁰)_(nn); or a pharmaceutically acceptable salt or solvatethereof; wherein: DRUG is a compound of formula 557:

wherein: nn is 1, 2 or 3; A⁰ is A¹, A² or W³ with the proviso that theconjugate includes at least one A¹;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A³ groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 2. The conjugateof claim 1 that is of formula 211 or 212:

or a pharmaceutically acceptable salt or solvate thereof; wherein: oneA⁰ is A¹.
 3. The conjugate of claim 1 wherein each A³ is of the formula:


4. The conjugate of claim 1 wherein each A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.
 5. The conjugate of claim 1 wherein each A³ is of the formula:

wherein: Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.
 6. The conjugateof claim 1 wherein A⁰ is of the formula:

wherein each R is independently alkyl.
 7. The conjugate of claim 2wherein each A³ is of the formula:


8. The conjugate of claim 2 wherein each A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.
 9. The conjugate of claim 2 wherein each A³ is of the formula:

wherein: Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.
 10. Theconjugate of claim 2 wherein A⁰ is of the formula:

wherein each R is independently alkyl.
 11. A pharmaceutical compositioncomprising a pharmaceutical excipient and a conjugate as described inclaim 1, or a pharmaceutically acceptable salt or solvate thereof.
 12. Apharmaceutical composition comprising a pharmaceutical excipient and aconjugate as described in claim 2, or a pharmaceutically acceptable saltor solvate thereof.